53 results on '"Tao Zf"'
Search Results
2. BCL-X L -targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.
- Author
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Judd AS, Bawa B, Buck WR, Tao ZF, Li Y, Mitten MJ, Bruncko M, Catron N, Doherty G, Durbin KR, Enright B, Frey R, Haasch D, Haman S, Haight AR, Henriques TA, Holms J, Izeradjene K, Judge RA, Jenkins GJ, Kunzer A, Leverson JD, Martin RL, Mitra D, Mittelstadt S, Nelson L, Nimmer P, Palma J, Peterson R, Phillips DC, Ralston SL, Rosenberg SH, Shen X, Song X, Vaidya KR, Wang X, Wang J, Xiao Y, Zhang H, Zhang X, Blomme EA, Boghaert ER, Kalvass JC, Phillips A, and Souers AJ
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Small Molecule Libraries pharmacology, bcl-X Protein antagonists & inhibitors, bcl-X Protein metabolism, Immunoconjugates pharmacology, Xenograft Model Antitumor Assays
- Abstract
Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X
L ) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-XL inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-XL inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-XL -targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-XL -mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-XL -targeting agent to enter human clinical trials.- Published
- 2024
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3. Incidence and warning signs for complications of human brucellosis: a multi-center observational study from China.
- Author
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Shi QN, Qin HJ, Lu QS, Li S, Tao ZF, Fan MG, Aishan MH, Kou ZQ, Chen QL, Yin WW, and Zhang YP
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- Humans, Middle Aged, Arthralgia complications, C-Reactive Protein analysis, C-Reactive Protein metabolism, Cross-Sectional Studies, Incidence, Retrospective Studies, Adult, Brucellosis complications, Brucellosis diagnosis, Brucellosis epidemiology, Delayed Diagnosis
- Abstract
Background: Brucellosis is a severe zoonotic disease that is often overlooked, particularly in impoverished countries. Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes. However, there is currently a lack of established indicators or biomarkers for diagnosing these complications. Therefore, this study aimed to investigate potential warning signs of focal complications in human brucellosis, with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients., Methods: A multi-center cross-sectional study was conducted in China from December 2019 to August 2021. The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a questionnaire survey and medical record system. The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used for variable screening and model evaluation., Results: A total of 880 participants diagnosed with human brucellosis were enrolled. The median age of the patients was 50 years [interquartile range (IQR): 41.5-58.0], and 54.8% had complications. The most common organ system affected by complications was the osteoarticular system (43.1%), with peripheral arthritis (30.0%), spondylitis (16.6%), paravertebral abscess (5.0%), and sacroiliitis (2.7%) being the most prevalent. Complications in other organ systems included the genitourinary system (4.7%), respiratory system (4.7%), and hematologic system (4.6%). Several factors were found to be associated with focal brucellosis. These factors included a long delay in diagnosis [odds ratio (OR) = 3.963, 95% confidence interval (CI) 1.906-8.238 for > 90 days], the presence of underlying disease (OR = 1.675, 95% CI 1.176-2.384), arthralgia (OR = 3.197, 95% CI 1.986-5.148), eye bulging pain (OR = 3.482, 95% CI 1.349-8.988), C-reactive protein (CRP) > 10 mg/L (OR = 1.910, 95% CI 1.310-2.784) and erythrocyte sedimentation rate (ESR) elevation (OR = 1.663, 95% CI 1.145-2.415). The optimal cutoff value in ROC analysis was > 5.4 mg/L for CRP (sensitivity 73.4% and specificity 51.9%) and > 25 mm/h for ESR (sensitivity 47.9% and specificity 71.1%)., Conclusions: More than 50% of patients with brucellosis experienced complications. Factors such as diagnostic delay, underlying disease, arthralgia, eye pain, and elevated levels of CRP and ESR were identified as significant markers for the development of complications. Therefore, patients presenting with these conditions should be closely monitored for potential complications, regardless of their culture results and standard tube agglutination test titers., (© 2024. The Author(s).)
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- 2024
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4. Diagnostic Accuracy of Prenatal Fetal Ultrasound to Detect Cleft Palate in High-Risk Fetuses: A Systematic Review and Meta-Analysis.
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Lai GP, Weng XJ, Wang M, Tao ZF, and Liao FH
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- Female, Fetus, Humans, Pregnancy, Sensitivity and Specificity, Ultrasonography, Prenatal, Cleft Lip diagnostic imaging, Cleft Palate diagnostic imaging
- Abstract
Objectives: This systematic review and meta-analysis investigated the accuracy of prenatal fetal ultrasound (US) to detect cleft palate during the second and third trimester (12-36 weeks) of pregnancy in high-risk fetuses., Methods: Pubmed and Embase databases were searched for studies that performed prenatal fetal US (comparator) and postnatal examination (reference standard) in fetuses at high risk for orofacial clefts. Risk of bias among included studies was assessed using the QUADAS-2. Area under the summary receiver operating characteristic (SROC) curve and pooled sensitivity and specificity were calculated., Results: This meta-analysis included 7 studies involving 663 high-risk fetuses. The individual studies showed that prenatal fetal US accurately predicted the possibility of cleft palate in these fetuses. Pooled sensitivity was 87% (95% CI 71%-95%), pooled specificity was 98% (95%CI 90%-100%), and the area under the SROC curve was 0.98 (95% CI 0.97-0.99)., Conclusion: Second and third trimester fetal US has excellent sensitivity and specificity for the detection of cleft palate in high-risk pregnancies., (© 2021 American Institute of Ultrasound in Medicine.)
- Published
- 2022
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5. Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.
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Salem AH, Tao ZF, Bueno OF, Chen J, Chen S, Edalji R, Elmore SW, Fournier KM, Harper KC, Hong R, Jenkins GJ, Ji J, Judge RA, Kalvass JC, Klix RC, Ku YY, Leverson JD, Marks RA, Marsh KC, Menon RM, Park CH, Phillips DC, Pu YM, Rosenberg SH, Sanzgiri YD, Sheikh AY, Shi Y, Stolarik D, Suleiman AA, Wang X, Zhang GGZ, Catron ND, and Souers AJ
- Subjects
- Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Line, Tumor, Cross-Over Studies, Female, Healthy Volunteers, Humans, Prodrugs pharmacology, Sulfonamides pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Prodrugs therapeutic use, Sulfonamides therapeutic use
- Abstract
Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug ( 3 , ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing., (©2021 American Association for Cancer Research.)
- Published
- 2021
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6. Structure-Based Design of A-1293102, a Potent and Selective BCL-X L Inhibitor.
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Tao ZF, Wang X, Chen J, Ingram JP, Jin S, Judge RA, Kovar PJ, Park C, Sun C, Wakefield BD, Zhou L, Zhang H, Elmore SW, Phillips DC, Judd AS, Leverson JD, and Souers AJ
- Abstract
BCL-X
L , an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-XL inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-XL inhibitor A-1155463 and the dual BCL-XL /BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-XL and both efficiently and selectively killed BCL-XL -dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-XL , while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-XL inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization., Competing Interests: The authors declare the following competing financial interest(s): AbbVie participated in interpretation of data and review and approval of publication. Z-F.T., X.W., J.C., J.P.I., S.J., R.A.J., P.J.K., C.S., B.D.W., L.Z., H.Z., S.W.E., D.C.P., A.S.J., J.D.L., and A.J.S. are employees of AbbVie; C.P. was an employee of AbbVie at the time of the study., (© 2021 American Chemical Society.)- Published
- 2021
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7. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X L Inhibitor.
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Wang L, Doherty GA, Judd AS, Tao ZF, Hansen TM, Frey RR, Song X, Bruncko M, Kunzer AR, Wang X, Wendt MD, Flygare JA, Catron ND, Judge RA, Park CH, Shekhar S, Phillips DC, Nimmer P, Smith ML, Tahir SK, Xiao Y, Xue J, Zhang H, Le PN, Mitten MJ, Boghaert ER, Gao W, Kovar P, Choo EF, Diaz D, Fairbrother WJ, Elmore SW, Sampath D, Leverson JD, and Souers AJ
- Abstract
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X
L inhibitor that selectively and potently induces apoptosis in BCL-XL -dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3 -rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL . A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program., Competing Interests: The authors declare the following competing financial interest(s): AbbVie and Genentech participated in interpretation of data and review and approval of publication. L.W., G.A.D., A.S.J., Z-F.T., T. M. H., R.R.F., X.S., M.B., A.R.K., X.W., M.D.W., N.D.C., S.S., D.C.P., R.A.J., P.N., M.L.S., S.K.T., Y.X., J.X., H.Z., P.N.L., M.J.M., E.R.B., W.G., P.K., S.W.E., J.D.L., and A.J.S. are employees of AbbVie, Inc. C.H.P. was an employee of AbbVie, Inc at the time of the study. E.C. and W.J.F. are employees of Genentech, Inc. J.A.F., D.D., and D.S. were employees of Genentech, Inc. at the time of the study.- Published
- 2020
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8. Correction to Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity.
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Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, Erickson S, Fidanze S, Fry E, Hasvold L, Jenkins GJ, Jin S, Judge RA, Kovar PJ, Madar D, Nimmer P, Park C, Petros AM, Rosenberg SH, Smith ML, Song X, Sun C, Tao ZF, Wang X, Xiao Y, Zhang H, Tse C, Leverson JD, Elmore SW, and Souers AJ
- Published
- 2015
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9. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA.
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Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ, Tao ZF, Song YC, Chen Q, and Jiang Q
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- Animals, Apoptosis, Binding, Competitive, Cells, Cultured, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Type 2 metabolism, Diabetic Retinopathy metabolism, Diabetic Retinopathy physiopathology, Electroretinography, Eye Proteins biosynthesis, Eye Proteins genetics, Feedback, Physiological, Gene Expression Profiling, Glucose pharmacology, Human Umbilical Vein Endothelial Cells, Humans, Macaca mulatta, Mice, Mice, Mutant Strains, MicroRNAs antagonists & inhibitors, MicroRNAs metabolism, RNA Interference, RNA, Long Noncoding antagonists & inhibitors, RNA, Long Noncoding biosynthesis, RNA, Long Noncoding genetics, Rats, Rats, Sprague-Dawley, Retina pathology, Vascular Endothelial Growth Factor A physiology, Diabetic Retinopathy genetics, Endothelial Cells metabolism, RNA, Long Noncoding physiology, Retina metabolism, Retinal Neovascularization genetics
- Abstract
Rationale: Pathological angiogenesis is a critical component of diseases, such as ocular disorders, cancers, and atherosclerosis. It is usually caused by the abnormal activity of biological processes, such as cell proliferation, cell motility, immune, or inflammation response. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of these biological processes. However, the role of lncRNA in diabetes mellitus-induced microvascular dysfunction is largely unknown., Objective: To elucidate whether lncRNA-myocardial infarction-associated transcript (MIAT) is involved in diabetes mellitus-induced microvascular dysfunction., Methods and Results: Using quantitative polymerase chain reaction, we demonstrated increased expression of lncRNA-MIAT in diabetic retinas and endothelial cells cultured in high glucose medium. Visual electrophysiology examination, TUNEL staining, retinal trypsin digestion, vascular permeability assay, and in vitro studies revealed that MIAT knockdown obviously ameliorated diabetes mellitus-induced retinal microvascular dysfunction in vivo, and inhibited endothelial cell proliferation, migration, and tube formation in vitro. Bioinformatics analysis, luciferase assay, RNA immunoprecipitation, and in vitro studies revealed that MIAT functioned as a competing endogenous RNA, and formed a feedback loop with vascular endothelial growth factor and miR-150-5p to regulate endothelial cell function., Conclusions: This study highlights the involvement of lncRNA-MIAT in pathological angiogenesis and facilitates the development of lncRNA-directed diagnostics and therapeutics against neovascular diseases., (© 2015 American Heart Association, Inc.)
- Published
- 2015
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10. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.
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Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, Belmont LD, Nimmer P, Xiao Y, Ma XM, Lowes KN, Kovar P, Chen J, Jin S, Smith M, Xue J, Zhang H, Oleksijew A, Magoc TJ, Vaidya KS, Albert DH, Tarrant JM, La N, Wang L, Tao ZF, Wendt MD, Sampath D, Rosenberg SH, Tse C, Huang DC, Fairbrother WJ, Elmore SW, and Souers AJ
- Subjects
- Administration, Oral, Aniline Compounds therapeutic use, Animals, Antineoplastic Agents therapeutic use, Benzothiazoles chemistry, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cell Line, Tumor, Cell Survival, Docetaxel, Gene Expression Profiling, Granulocytes metabolism, Humans, Isoquinolines chemistry, Kinetics, Mice, Neoplasm Transplantation, Neoplasms metabolism, Neutropenia chemically induced, Neutrophils drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, Sulfonamides therapeutic use, Taxoids adverse effects, Thrombocytopenia chemically induced, bcl-X Protein antagonists & inhibitors, bcl-X Protein metabolism, Gene Expression Regulation, Neoplastic, Neoplasms drug therapy, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
- Abstract
The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
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11. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.
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Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, Erickson S, Fidanze S, Fry E, Hasvold L, Jenkins GJ, Jin S, Judge RA, Kovar PJ, Madar D, Nimmer P, Park C, Petros AM, Rosenberg SH, Smith ML, Song X, Sun C, Tao ZF, Wang X, Xiao Y, Zhang H, Tse C, Leverson JD, Elmore SW, and Souers AJ
- Subjects
- Apoptosis drug effects, Cell Survival drug effects, Crystallography, X-Ray, Databases, Factual, High-Throughput Screening Assays, Humans, Molecular Docking Simulation, Molecular Structure, Multiple Myeloma metabolism, Multiple Myeloma pathology, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Protein Binding, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Drug Design, Multiple Myeloma drug therapy, Myeloid Cell Leukemia Sequence 1 Protein chemistry, Pancreatic Neoplasms drug therapy
- Abstract
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
- Published
- 2015
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12. Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.
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Tao ZF, Hasvold L, Wang L, Wang X, Petros AM, Park CH, Boghaert ER, Catron ND, Chen J, Colman PM, Czabotar PE, Deshayes K, Fairbrother WJ, Flygare JA, Hymowitz SG, Jin S, Judge RA, Koehler MF, Kovar PJ, Lessene G, Mitten MJ, Ndubaku CO, Nimmer P, Purkey HE, Oleksijew A, Phillips DC, Sleebs BE, Smith BJ, Smith ML, Tahir SK, Watson KG, Xiao Y, Xue J, Zhang H, Zobel K, Rosenberg SH, Tse C, Leverson JD, Elmore SW, and Souers AJ
- Abstract
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.
- Published
- 2014
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13. Epigenetics and ocular diseases: from basic biology to clinical study.
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Yan B, Yao J, Tao ZF, and Jiang Q
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- Aging genetics, Aging pathology, Chromatin Assembly and Disassembly genetics, Eye metabolism, Eye Diseases etiology, Eye Diseases pathology, Gene Expression Regulation, Humans, RNA, Untranslated genetics, DNA Methylation genetics, Epigenesis, Genetic, Eye growth & development, Eye Diseases genetics
- Abstract
Epigenetics is an emerging field in ophthalmology and has opened a new avenue for understanding ocular development and ocular diseases related to aging and environment. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and deployment of non-coding RNAs, result in the heritable silencing of gene expression without any change in DNA sequence. Accumulating evidence suggests a potential link between gene expression, chromatin structure, non-coding RNAs, and cellular differentiation during ocular development. Disruption of the balance of epigenetic networks could become the etiology of several ocular diseases. Here, we summarized the current knowledge about epigenetic regulatory mechanisms in ocular development and diseases., (© 2013 Wiley Periodicals, Inc.)
- Published
- 2014
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14. Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL.
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Koehler MF, Bergeron P, Choo EF, Lau K, Ndubaku C, Dudley D, Gibbons P, Sleebs BE, Rye CS, Nikolakopoulos G, Bui C, Kulasegaram S, Kersten WJ, Smith BJ, Czabotar PE, Colman PM, Huang DC, Baell JB, Watson KG, Hasvold L, Tao ZF, Wang L, Souers AJ, Elmore SW, Flygare JA, Fairbrother WJ, and Lessene G
- Abstract
Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.
- Published
- 2014
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15. Aberrant expression of long noncoding RNAs in early diabetic retinopathy.
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Yan B, Tao ZF, Li XM, Zhang H, Yao J, and Jiang Q
- Subjects
- Animals, Blood Glucose metabolism, Female, Gene Expression Profiling, Male, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Retina metabolism, Diabetes Mellitus, Experimental genetics, Diabetic Retinopathy genetics, Gene Expression Regulation physiology, RNA, Long Noncoding genetics
- Abstract
Purpose: Long noncoding RNAs (lncRNAs) are broadly classified as transcripts longer than 200 nucleotides. lncRNA-mediated biology has been implicated in a variety of cellular processes and human diseases. Diabetic retinopathy (DR) is one of the leading causes of blindness. However, little is known about the role of lncRNAs in DR The goal of this study aimed to identify lncRNAs involved in early DR and characterize their roles in DR pathogenesis., Methods: We established a mouse model of streptozotocin (STZ)-induced diabetes, and performed lncRNA expression profiling of retinas using microarray analysis. Based on the Pearson correlation analysis, an lncRNA/mRNA coexpression network was constructed. Gene ontology (GO) enrichment and KEGG analysis of lncRNAs-coexpressed mRNAs was conducted to identify the related biological modules and pathologic pathways. Real-time PCR was conducted to detect the expression pattern of lncRNA in the clinical samples and the RF/6A cell model of hyperglycemia., Results: Approximately 303 lncRNAs were aberrantly expressed in the retinas of early DR, including 214 downregulated lncRNAs and 89 upregulated lncRNAs. GO analysis indicated that these lncRNAs-coexpressed mRNAs were targeted to eye development process (ontology: biological process), integral to membrane (ontology: cellular component), and structural molecule activity (ontology: molecular function). Pathway analysis indicated that lncRNAs-coexpressed mRNAs were mostly enriched in axon guidance signaling pathway. In addition, MALAT1, a conserved lncRNA, was significantly upregulated in an RF/6A cell model of hyperglycemia, in the aqueous humor samples, and in fibrovascular membranes of diabetic patients., Conclusions: lncRNAs are involved in the pathogenesis of DR through the modulation of multiple pathogenetic pathways. MALAT1, a conserved lncRNA, may become a potential therapeutic target for the prognosis, diagnosis, and treatment of DR.
- Published
- 2014
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16. Regulation of autophagy by high glucose in human retinal pigment epithelium.
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Yao J, Tao ZF, Li CP, Li XM, Cao GF, Jiang Q, and Yan B
- Subjects
- Biomarkers metabolism, Endoplasmic Reticulum Stress drug effects, Humans, Reactive Oxygen Species metabolism, Retinal Pigment Epithelium drug effects, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium ultrastructure, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Autophagy drug effects, Glucose pharmacology, Retinal Pigment Epithelium cytology
- Abstract
Background: Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Retinal pigment epithelium (RPE) works as the outer blood retina barrier and is vulnerable to energy stress-induced injury. However, the effect of high glucose treatment on autophagy is still unclear in RPE., Methods: Transmission electron microscopy was used to detect the generation of autophagosome. Small interfering RNA (siRNA) and MTT was used to determine the effect of autophagy on cell viability. Western blots and immunohistochemistry were used to detect the expression pattern of autophagic markers, including LC3 and p62., Results: High glucose treatment results in a significant increase in the generation of autophagosome and altered expression of LC3 and p62. High glucose-induced autophagy is independent of mTOR signaling, but is mainly regulated via ROS-mediated ER stress signaling., Conclusion: In the scenario of high glucose-induced oxidative stress, autophagy may be required for the removal of damaged proteins, and provide a default mechanism to prevent high glucose-induced injury in RPE.
- Published
- 2014
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17. Long noncoding RNAs: versatile players in biologcial processes and human disorders.
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Yan B, Wang ZH, Liu JY, Tao ZF, Li XM, and Qin J
- Published
- 2014
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18. Epigallocatechin-gallate (EGCG) regulates autophagy in human retinal pigment epithelial cells: a potential role for reducing UVB light-induced retinal damage.
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Li CP, Yao J, Tao ZF, Li XM, Jiang Q, and Yan B
- Subjects
- Catechin therapeutic use, Cell Line, Humans, Retinal Pigment Epithelium radiation effects, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Ultraviolet Rays, Antioxidants therapeutic use, Autophagy drug effects, Autophagy radiation effects, Catechin analogs & derivatives, Retinal Pigment Epithelium drug effects, Retinal Pigment Epithelium pathology
- Abstract
Autophagy is an intracellular catabolic process involved in protein and organelle degradation via the lysosomal pathway that has been linked in the pathogenesis of age-related macular degeneration (AMD). UVB irradiation-mediated degeneration of the macular retinal pigment epithelial (RPE) cells is an important hallmark of AMD, which is along with the change in RPE autophagy. Thus, pharmacological manipulation of RPE autophagy may offer an alternative therapeutic target in AMD. Here, we found that epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, plays a regulatory role in UVB irradiation-induced autophagy in RPE cells. UVB irradiation results in a marked increase in the amount of LC3-II protein in a dose-dependent manner. EGCG administration leads to a significant reduction in the formation of LC3-II and autophagosomes. mTOR signaling activation is required for EGCG-induced LC3-II formation, as evidenced by the fact that EGCG-induced LC3-II formation is significantly impaired by rapamycin administration. Moreover, EGCG significantly alleviates the toxic effects of UVB irradiation on RPE cells in an autophagy-dependent manner. Collectively, our study reveals a novel role of EGCG in RPE autophagy. EGCG may be exploited as a potential therapeutic reagent for the treatment of pathological conditions associated with abnormal autophagy., (Published by Elsevier Inc.)
- Published
- 2013
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19. Value of postoperative radiation therapy for regional control after dissection in head and neck squamous cell carcinoma cases.
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Li XM, Di B, Shang YD, Tao ZF, Cheng JM, and He ZG
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell radiotherapy, Carcinoma, Squamous Cell surgery, Combined Modality Therapy, Female, Follow-Up Studies, Head and Neck Neoplasms surgery, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local radiotherapy, Neoplasm Recurrence, Local surgery, Neoplasm Staging, Postoperative Period, Prognosis, Retrospective Studies, Survival Rate, Head and Neck Neoplasms mortality, Head and Neck Neoplasms radiotherapy, Neck Dissection mortality, Radiotherapy, Adjuvant mortality
- Abstract
Objective: We aimed to define clinicopathologic risk factors associated with regional recurrence (RR) and thus the effectiveness of postoperative radiotherapy (PORT) for neck control for head and neck squamous cell carcinomas (HNSCCs) with differing cervical lymph node status., Methods: A retrospective study was performed in 196 HNSCC patients with pathologically positive neck node (N+) to evaluate the high-risk factors for RR and to define the role of PORT in control after neck dissection and postoperative radiotherapy (PORT)., Results: Overall, the RR rate after neck dissection and PORT was 29%. Extracapsular spread (ECS) was confirmed to be the only independent risk factor for RR. There were no significant risk factors associated with RR in the ECS- group. The 5-year disease-specific survival rate was 45%, which descended to 10% with the emergence of RR., Conclusions: ECS remains a determined risk factor for RR after neck dissection and PORT in patients with N+. PORT alone is not adequate for preventing RR in the neck with ECS after neck dissection. More intensive postoperative adjuvant therapies, especially combined chemotherapy and radiotherapy, are needed to prevent regional failure in HNSCC patients with ECS.
- Published
- 2013
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20. Overexpression of synoviolin facilitates the formation of a functional synovial biomembrane.
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Chen G, Zhang SX, Tao ZF, Xiong Y, Sun W, Lu J, Pan F, and Zhang ZZ
- Subjects
- Animals, Base Sequence, Coculture Techniques, DNA Primers, Enzyme-Linked Immunosorbent Assay, Hyaluronic Acid metabolism, Lentivirus genetics, Microscopy, Electron, Scanning, Rabbits, Reverse Transcriptase Polymerase Chain Reaction, Tendons surgery, Tumor Suppressor Protein p53 metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitination, Cell Membrane, Synovial Membrane metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Digital flexor tendon repair poses a significant challenge for hand surgeons. Currently, extrasynovial tendon grafts are frequently used in clinical settings to bridge flexor tendon defects. However, the healing process is always accompanied by postoperative adhesion. This is mostly due to the fact that no synovial membrane covers the extrasynovial tendon surface, in contrast to the intrasynovial tendon. In this study, we present an efficient method of developing a functional synovial biomembrane on the surface of the extrasynovial tendon. Synoviocytes were isolated from the knee joint of a Japanese white rabbit. After being infected with lentivirus, the over-expression of synoviolin in these synoviocytes was confirmed by semi-quantitative RT-PCR and western blotting. Cellular proliferation and increased hyaluronic acid secretion were confirmed in the synoviolin over-expressing synoviocytes by MTT-based method, cell cycle assays and ELISA. Furthermore, the synoviolin over-expressing synoviocytes were co-cultured with extrasynovial tendons that were harvested from the hind leg of rabbits. After being co-cultured in vitro for 3 and 7 days, these infected synoviocytes were found to accelerate the formation of a biomembrane on the tendon surface compared to the control group. More importantly, Alcian blue staining confirmed the ability of this cultured biomembrane to produce specific matrices containing acidic carboxyl mucopolysaccharides (mainly hyaluronic acid). All these results demonstrate that the over-expression of synoviolin stimulates the proliferation and HA secretion of synoviocytes and facilitates the formation of a functional synovial biomembrane., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
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21. Changes of synaptic ultrastructure in the guinea pig interpositus nuclei associate with response magnitude and timing after trace eyeblink conditioning.
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Hu B, Chen H, Yang L, Tao ZF, Yan J, Zhang YH, Zhu ZR, Sun WZ, Huang W, Huang WQ, and Sui JF
- Subjects
- Animals, Cerebellum physiology, Guinea Pigs, Male, Microscopy, Electron, Transmission methods, Microscopy, Electron, Transmission statistics & numerical data, Synapses physiology, Cerebellum ultrastructure, Conditioning, Eyelid physiology, Post-Synaptic Density physiology, Post-Synaptic Density ultrastructure, Synapses ultrastructure
- Abstract
Learning-induced changes of synaptic ultrastructure have long been proposed as a mechanism that may contribute to support memory formation. Although recent studies have demonstrated that the interpositus nuclei (IN) play critical role in acquisition and retention of trace conditioned eyeblink responses (CRs), there is now limited evidence associating trace eyeblink conditioning with changes of synaptic ultrastructure in the IN. Here, we investigated this issue using a transmission electron microscope. Adult guinea pigs were randomly allocated to either a trace-paired, delay-paired, unpaired or exposure-only condition. The IN tissue was taken for morphological analysis 1h after the completion of the tenth training session. Serial section analysis of synaptic ultrastructure revealed that trace eyeblink conditioning induced increases in the thickness of excitatory PSD. Classification of the synapses into shape subtypes indicated that the increased thickness of excitatory PSD was mainly attributable to increase in the concave- and convex-shaped synapses. On the contrary, trace eyeblink conditioning resulted in decreases in the thickness of inhibitory PSD. Specifically, these significant changes of PSD thickness were limited to occur in the animals with good behavioral performance. Further analysis of correlations between the trace CR performance and synaptic ultrastructural modifications showed that the thickness of excitatory PSD within the IN correlated with the peak amplitude of trace CRs, whereas the thickness of inhibitory PSD correlated with the onset latency. The present findings suggest that trace eyeblink conditioning induces structural plasticity in the IN, which may play a crucial role in acquiring and executing adaptive eyeblink movements., (Copyright © 2011 Elsevier B.V. All rights reserved.)
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- 2012
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22. The electromagnetic-trait imaging computation of traveling wave method in breast tumor microwave sensor system.
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Tao ZF, Han ZL, and Yao M
- Subjects
- Algorithms, Computational Biology, Computer Simulation, Diagnostic Imaging methods, Diagnostic Imaging statistics & numerical data, Electromagnetic Phenomena, Female, Humans, Phantoms, Imaging, Breast Neoplasms diagnosis, Microwaves
- Abstract
Using the difference of dielectric constant between malignant tumor tissue and normal breast tissue, breast tumor microwave sensor system (BRATUMASS) determines the detected target of imaging electromagnetic trait by analyzing the properties of target tissue back wave obtained after near-field microwave radicalization (conelrad). The key of obtained target properties relationship and reconstructed detected space is to analyze the characteristics of the whole process from microwave transmission to back wave reception. Using traveling wave method, we derive spatial transmission properties and the relationship of the relation detected points distances, and valuate the properties of each unit by statistical valuation theory. This chapter gives the experimental data analysis results.
- Published
- 2011
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23. Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as potent, highly selective, and orally bioavailable inhibitors of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM) kinases.
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Tao ZF, Hasvold LA, Leverson JD, Han EK, Guan R, Johnson EF, Stoll VS, Stewart KD, Stamper G, Soni N, Bouska JJ, Luo Y, Sowin TJ, Lin NH, Giranda VS, Rosenberg SH, and Penning TD
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Biological Availability, Cell Line, Tumor, Cell Membrane Permeability, Humans, In Vitro Techniques, Mice, Microsomes, Liver metabolism, Models, Molecular, Phosphorylation, Protein Conformation, Proto-Oncogene Proteins c-pim-1 chemistry, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Pyrimidinones pharmacokinetics, Pyrimidinones pharmacology, Structure-Activity Relationship, Thiophenes pharmacokinetics, Thiophenes pharmacology, bcl-Associated Death Protein metabolism, Antineoplastic Agents chemical synthesis, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Pyrimidines chemical synthesis, Pyrimidinones chemical synthesis, Thiophenes chemical synthesis
- Abstract
Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K(i) values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC(50) values. For example, compound 14j inhibited the growth of K562 cells with an EC(50) value of 1.7 muM and showed K(i) values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein binding, and no CYP inhibition below 20 muM concentration.
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- 2009
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24. Cyclin B1 is an efficacy-predicting biomarker for Chk1 inhibitors.
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Xiao Z, Xue J, Gu WZ, Bui M, Li G, Tao ZF, Lin NH, Sowin TJ, and Zhang H
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- Animals, Apoptosis drug effects, Biomarkers metabolism, Cell Proliferation drug effects, Checkpoint Kinase 1, Cyclin B1, DNA Topoisomerases metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Female, HeLa Cells, Histones metabolism, Humans, Male, Mice, Mice, SCID, Mitosis drug effects, Neoplasms drug therapy, Neoplasms enzymology, Neoplasms genetics, Neoplasms pathology, Phosphorylation, Protein Kinase Inhibitors administration & dosage, Protein Kinases genetics, Time Factors, Transfection, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cyclin B metabolism, Genetic Therapy methods, Neoplasms therapy, Protein Kinases metabolism, RNA Interference, RNA, Small Interfering metabolism, Topoisomerase Inhibitors
- Abstract
Chk1 is the major mediator of cell-cycle checkpoints in response to various forms of genotoxic stress. Although it was previously speculated that checkpoint abrogation due to Chk1 inhibition may potentiate the efficacy of DNA-damaging agents through induction of mitotic catastrophe, there has not been direct evidence proving this process. Here, through both molecular marker and morphological analysis, we directly demonstrate that specific downregulation of Chk1 expression by Chk1 siRNA potentiates the cytotoxicities of topoisomerase inhibitors through the induction of premature chromosomal condensation and mitotic catastrophe. More importantly, we discovered that the cellular cyclin B1 level is the major determinant of the potentiation. We show that downregulation of cyclin B1 leads to impairment of the induction of mitotic catastrophe and correspondingly a reduction of the potentiation ability of either Chk1 siRNA or a small molecule Chk1 inhibitor. More significantly, we have extended the study by examining a panel of 10 cancer cell-lines with different tissue origins for their endogenous levels of cyclin B1 and the ability of a Chk1 inhibitor to sensitize the cells to DNA-damaging agents. The cellular levels of cyclin B1 positively correlate with the degrees of potentiation achieved. Of additional interest, we observed that the various colon cancer cell lines in general appear to express higher levels of cyclin B1 and also display higher sensitivity to Chk1 inhibitors, implying that Chk1 inhibitor may be more efficacious in treating colon cancers. In summary, we propose that cyclin B1 is a biomarker predictive of the efficacy of Chk1 inhibitors across different types of cancers. Unlike previously established efficacy-predictive biomarkers that are usually the direct targets of the therapeutic agents, cyclin B1 represents a non-drug-target biomarker that is based on the mechanism of action of the target inhibitor. This finding may be potentially very useful for the stratification of patients for Chk1 inhibitor clinical trials and hence, maximize its chance of success.
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- 2008
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25. Synthesis and in-vitro biological activity of macrocyclic urea Chk1 inhibitors.
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Li G, Tao ZF, Tong Y, Przytulinska MK, Kovar P, Merta P, Chen Z, Zhang H, Sowin T, Rosenberg SH, and Lin NH
- Subjects
- Cell Line, Tumor, Checkpoint Kinase 1, HeLa Cells, Humans, Macrocyclic Compounds pharmacology, Protein Kinase Inhibitors pharmacology, Structure-Activity Relationship, Urea pharmacology, Macrocyclic Compounds chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Protein Kinases metabolism, Urea chemical synthesis
- Abstract
A variety of macrocyclic urea compounds were prepared as potent Chk1 inhibitors by modifying the C5 position of the benzene ring of the macrocyclic urea with ether moieties, aliphatic carbon chains, amide and halides. Enzymatic activity less than 20nM was observed in 29 of 40 compounds. Compounds 14, 46d, and 48j provided the best overall results in the cellular assays as they abrogated doxorubicin-induced cell cycle arrest (IC(50)=3.31, 3.08, and 3.13microM) and enhanced doxorubicin cytotoxicity (IC(50)=0.54, 1.27, and 0.96microM) while displaying no single agent activity, respectively.
- Published
- 2007
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26. Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics.
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Tao ZF, Chen Z, Bui MH, Kovar P, Johnson E, Bouska J, Zhang H, Rosenberg S, Sowin T, and Lin NH
- Subjects
- Animals, Catalysis, Checkpoint Kinase 1, HeLa Cells, Humans, Macrocyclic Compounds pharmacology, Mice, Protein Kinase Inhibitors pharmacology, Structure-Activity Relationship, Urea pharmacology, Macrocyclic Compounds chemical synthesis, Macrocyclic Compounds pharmacokinetics, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Protein Kinases pharmacokinetics, Protein Kinases physiology, Urea chemical synthesis, Urea pharmacokinetics
- Abstract
A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome profiling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl)ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies.
- Published
- 2007
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27. Discovery of 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2'-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors.
- Author
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Tao ZF, Li G, Tong Y, Stewart KD, Chen Z, Bui MH, Merta P, Park C, Kovar P, Zhang H, Sham HL, Rosenberg SH, Sowin TJ, and Lin NH
- Subjects
- Checkpoint Kinase 1, Nitriles chemistry, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Nitriles pharmacology, Protein Kinase Inhibitors pharmacology, Protein Kinases drug effects
- Abstract
An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing.
- Published
- 2007
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28. Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: improving oral biovailability.
- Author
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Tong Y, Przytulinska M, Tao ZF, Bouska J, Stewart KD, Park C, Li G, Claiborne A, Kovar P, Chen Z, Merta PJ, Bui MH, Olson A, Osterling D, Zhang H, Sham HL, Rosenberg SH, Sowin TJ, and Lin NH
- Subjects
- Administration, Oral, Animals, Checkpoint Kinase 1, Cyanides chemistry, Indenes chemistry, Inhibitory Concentration 50, Mice, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Pyrazoles administration & dosage, Pyrazoles chemical synthesis, Rats, Structure-Activity Relationship, Hydrogen chemistry, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism, Pyrazoles chemistry, Pyrazoles pharmacology, Pyridines chemistry
- Abstract
A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.
- Published
- 2007
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29. Prognostic factors and staging systems of multiple myeloma:.
- Author
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Tao ZF, Fu WJ, Yuan ZG, Wang DX, Chen YB, and Hou J
- Subjects
- Adult, Aged, C-Reactive Protein analysis, Female, Humans, Interleukin-6 blood, Male, Middle Aged, Multiple Myeloma blood, Multiple Myeloma pathology, Multivariate Analysis, Neoplasm Staging, Prognosis, Survival Rate, Multiple Myeloma mortality
- Abstract
Background: Previous studies found a range of prognostic factors but no consensus about the proper staging system for multiple myeloma has been achieved. This study explored the prognostic factors to find a staging system for multiple myeloma most suitable for Chinese patients., Methods: Between February 1990 to August 2004, 206 patients (138 men and 68 women, mean aged (59 +/- 11) years) who were initially diagnosed as multiple myeloma in Changzheng Hospital (Shanghai, China) and had followup records were enrolled in this study. Potential prognostic factors were evaluated by univariate and multivariate analyses. Four staging systems were applied to compare their suitability for the patients., Results: The median survival time of the patients was 33 months. The 1-, 3- and 5-year survival rates were 80.18%, 48.08% and 33.7% respectively. Factors identified as adversely affecting survival were older age, severe bone lesions, low haemoglobin, low platelet, low serum calcium, low serum albumin, high proportion of plasma cells in marrow, high serum creatinine, high serum beta(2) microglobulin and high C-reactive protein. Among these, only C-reactive protein, beta(2) microglobulin, albumin and age were the independent prognostic factors. There were statistically significant survival differences among the three groups in Durie Salmon staging system and Bataille staging system, but not in British Medical Research Council staging system or International Staging System., Conclusions: High beta(2) microglobulin, high C-reactive protein, low albumin and old age are independent prognostic factors of multiple myeloma. Bataille staging system appears to be optimal for Chinese multiple myeloma patients.
- Published
- 2007
30. Design, synthesis, and biological activity of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one-based potent and selective Chk-1 inhibitors.
- Author
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Wang L, Sullivan GM, Hexamer LA, Hasvold LA, Thalji R, Przytulinska M, Tao ZF, Li G, Chen Z, Xiao Z, Gu WZ, Xue J, Bui MH, Merta P, Kovar P, Bouska JJ, Zhang H, Park C, Stewart KD, Sham HL, Sowin TJ, Rosenberg SH, and Lin NH
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Azepines chemistry, Azepines pharmacology, Benzodiazepinones chemistry, Benzodiazepinones pharmacology, Biological Availability, Camptothecin pharmacology, Cell Line, Tumor, Checkpoint Kinase 1, Crystallography, X-Ray, Doxorubicin pharmacology, Drug Design, Drug Synergism, Humans, Mice, Models, Molecular, Protein Binding, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Azepines chemical synthesis, Benzodiazepinones chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Protein Kinases metabolism
- Abstract
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.
- Published
- 2007
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31. Synthesis and biological evaluation of 4'-(6,7-disubstituted-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol as potent Chk1 inhibitors.
- Author
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Tao ZF, Li G, Tong Y, Chen Z, Merta P, Kovar P, Zhang H, Rosenberg SH, Sham HL, Sowin TJ, and Lin NH
- Subjects
- Checkpoint Kinase 1, Drug Evaluation, Preclinical, HeLa Cells, Humans, Protein Kinase Inhibitors chemistry, Pyrazoles chemistry, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Protein Kinases drug effects, Pyrazoles chemical synthesis, Pyrazoles pharmacology
- Abstract
A new series of potent tricyclic pyrazole-based Chk1 inhibitors are described. Analogues disubstituted on the 6- and 7-positions show improved Chk1 inhibition potency compared with analogues with a single substituent on either the 6- or 7-position. Based on the lead compound 4'-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol (2), detailed SAR studies on the 6- and 7-positions were performed. 3'-morpholin-4'-yl-propoxy, pyridin-4'-ylmethoxy, pyridin-3'-ylmethoxy, 2'-(5''-ethyl-pyridin-2''-yl)-ethoxy, pyridin-2'-ylethoxy, (6'-methyl-pyridin-2'-yl)-propoxyethoxy, 2',3'-dihydroxyl-1'-yl-propoxy, and tetrahydro-furan-3'-yloxy have been identified as the best groups on the 6-position when the 7-position is substituted with methoxyl group. Pyridin-2'-ylmethoxy and pyridin-3'-ylmethoxy have been identified as the best substituents at the 7-position while the 6-position bearing methoxyl group. These compounds significantly potentiate the cytotoxicity of DNA-damaging antitumor agents in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and the camptothecin-induced S checkpoints, suggesting that their potent biological activities are mechanism-based through Chk1 inhibition.
- Published
- 2007
- Full Text
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32. 1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: extended exploration on phenyl ring substitutions and preliminary ADME/PK studies.
- Author
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Tong Y, Claiborne A, Pyzytulinska M, Tao ZF, Stewart KD, Kovar P, Chen Z, Credo RB, Guan R, Merta PJ, Zhang H, Bouska J, Everitt EA, Murry BP, Hickman D, Stratton TJ, Wu J, Rosenberg SH, Sham HL, Sowin TJ, and Lin NH
- Subjects
- Animals, Antineoplastic Agents chemistry, Caco-2 Cells, Checkpoint Kinase 1, DNA Damage, Drug Design, Flow Cytometry, Humans, Inhibitory Concentration 50, Mice, Microsomes, Liver metabolism, Protein Kinase Inhibitors chemistry, Protein Kinases metabolism, Rats, Antineoplastic Agents pharmacokinetics, Chemistry, Pharmaceutical methods, Drug Screening Assays, Antitumor, Protein Kinase Inhibitors pharmacokinetics, Protein Kinases chemistry
- Abstract
A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC(50) values below 0.3nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed.
- Published
- 2007
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33. Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors.
- Author
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Tao ZF, Wang L, Stewart KD, Chen Z, Gu W, Bui MH, Merta P, Zhang H, Kovar P, Johnson E, Park C, Judge R, Rosenberg S, Sowin T, and Lin NH
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Camptothecin pharmacology, Cell Line, Tumor, Checkpoint Kinase 1, Crystallography, X-Ray, DNA Damage, Doxorubicin pharmacology, Drug Design, Drug Screening Assays, Antitumor, Drug Synergism, Humans, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Models, Molecular, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism, Structure-Activity Relationship, Urea chemistry, Urea pharmacology, Antineoplastic Agents chemical synthesis, Macrocyclic Compounds chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Protein Kinases chemistry, Urea analogs & derivatives, Urea chemical synthesis
- Abstract
Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
- Published
- 2007
- Full Text
- View/download PDF
34. Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics.
- Author
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Chen Z, Xiao Z, Gu WZ, Xue J, Bui MH, Kovar P, Li G, Wang G, Tao ZF, Tong Y, Lin NH, Sham HL, Wang JY, Sowin TJ, Rosenberg SH, and Zhang H
- Subjects
- Antibodies pharmacology, Blotting, Western, CDC2 Protein Kinase immunology, CDC2 Protein Kinase metabolism, Camptothecin pharmacology, Caspases metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation radiation effects, Cell Survival drug effects, Cell Survival radiation effects, Checkpoint Kinase 1, DNA Damage, Dose-Response Relationship, Drug, Doxorubicin pharmacology, Drug Synergism, HeLa Cells, Humans, Molecular Structure, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Phosphorylation drug effects, Protein Kinase Inhibitors chemistry, Protein Kinases genetics, Protein Kinases immunology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, RNA, Small Interfering genetics, Time Factors, Tumor Suppressor Protein p53 genetics, Urea chemistry, Urea pharmacology, cdc25 Phosphatases genetics, cdc25 Phosphatases metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism, Tumor Suppressor Protein p53 deficiency, Urea analogs & derivatives
- Abstract
The majority of cancer therapeutics induces DNA damage to kill cells. Normal proliferating cells undergo cell cycle arrest in response to DNA damage, thus allowing DNA repair to protect the genome. DNA damage induced cell cycle arrest depends on an evolutionarily conserved signal transduction network in which the Chk1 kinase plays a critical role. In mammalian cells, the p53 and RB pathways further augment the cell cycle arrest response to prevent catastrophic cell death. Given the fact that most tumor cells suffer defects in the p53 and RB pathways, it is likely that tumor cells would depend more on the Chk1 kinase to maintain cell cycle arrest than would normal cells. Therefore Chk1 inhibition could be used to specifically sensitize tumor cells to DNA-damaging agents. We have previously shown that siRNA-mediated Chk1 knockdown abrogates DNA damage-induced checkpoints and potentiates the cytotoxicity of several DNA-damaging agents in p53-deficient cell lines. In this study, we have developed 2 potent and selective Chk1 inhibitors, A-690002 and A-641397, and shown that these compounds abrogate cell cycle checkpoints and potentiate the cytotoxicity of topoisomerase inhibitors and gamma-radiation in p53-deficient but not in p53-proficient cells of different tissue origins. These results indicate that it is feasible to achieve a therapeutic window with 1 or more Chk1 inhibitors in potentiation of cancer therapy based on the status of the p53 pathway in a wide spectrum of tumor types., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
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35. An efficient mammalian transfer RNA target for bleomycin.
- Author
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Tao ZF, Konishi K, Keith G, and Hecht SM
- Subjects
- Animals, Chickens, Chromatography, Liquid, Electrophoresis, Polyacrylamide Gel, Magnesium chemistry, Mammals, Nucleic Acid Conformation, RNA, Transfer chemistry, Bleomycin pharmacology, RNA, Transfer drug effects
- Abstract
The antitumor antibiotic bleomycin has long been believed to exert its therapeutic effects at the level of DNA cleavage. Recently, evidence has been presented to suggest that RNA cleavage may also be important and that one or more transfer RNAs may be involved. To define those tRNAs that may represent important loci for the action of bleomycin, we have fractionated chicken liver tRNAs and identified those isoacceptors most susceptible to oxidative cleavage by Fe(II).BLM. Two chicken liver tRNAs, tRNA3Lys and tRNAPhe, were found to be cleaved with exceptional facility by Fe(II).BLM, and both were cleaved predominantly at U66. The cleavage of tRNA3Lys was shown to be minimally affected by physiological concentrations of Mg2+. Chicken liver tRNA3Lys is identical in sequence with human tRNA3Lys. These findings support a possible role for a critical tRNA such as tRNA3Lys in the mechanism by which bleomycin mediates its antitumor activity.
- Published
- 2006
- Full Text
- View/download PDF
36. Chk1 inhibitors for novel cancer treatment.
- Author
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Tao ZF and Lin NH
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents therapeutic use, Checkpoint Kinase 1, Chemotherapy, Adjuvant methods, Clinical Trials, Phase I as Topic, Drug Synergism, Humans, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors therapeutic use, Protein Kinases drug effects, Antineoplastic Agents chemistry, Cell Cycle drug effects, DNA Damage drug effects, Protein Kinase Inhibitors chemistry, Protein Kinases metabolism
- Abstract
Chemo- and radiotherapies that target DNA are the mainstay of cancer treatment. In response to DNA damage, cells are arrested in multiple checkpoints in the cell cycle to allow the damaged DNA to be repaired before progressing into mitosis. Normal cells are arrested in the G1 phase mediated by the p53 tumor suppressor, and p53-deficient cancer cells are arrested in the S or G2 phase. Checkpoint kinase 1 (Chk 1) is a serine / threonine protein kinase and a key mediator in the DNA damage-induced checkpoint network. When the G2 or S checkpoint is abrogated by the inhibition of Chk1, p53-deficient cancer cells undergo mitotic catastrophe and eventually apoptosis, whereas normal cells are still arrested in the G1 phase. Thus, Chk1 inhibitors can preferentially potentiate the efficacy of DNA damaging agents in cancer cells, and Chk1 is an attractive therapeutic target for cancer treatment, especially since approximately 50% of all human cancers are p53-deficient. This review discusses the rationale of Chk1 as an anticancer target, the structural basis for designing Chk1 inhibitors, and recently disclosed Chk1 inhibitors.
- Published
- 2006
- Full Text
- View/download PDF
37. Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors.
- Author
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Li G, Hasvold LA, Tao ZF, Wang GT, Gwaltney SL 2nd, Patel J, Kovar P, Credo RB, Chen Z, Zhang H, Park C, Sham HL, Sowin T, Rosenberg SH, and Lin NH
- Subjects
- Antibiotics, Antineoplastic chemical synthesis, Checkpoint Kinase 1, Crystallography, X-Ray, Doxorubicin pharmacology, Humans, Inhibitory Concentration 50, Nitriles chemical synthesis, Nitriles pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinases metabolism, Pyrazines chemical synthesis, Pyrazines pharmacology, Tumor Cells, Cultured, Urea analogs & derivatives, Urea chemical synthesis, Urea pharmacology, Antibiotics, Antineoplastic pharmacology, Cell Cycle drug effects, Protein Kinase Inhibitors pharmacology, Protein Kinases drug effects
- Abstract
Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.
- Published
- 2006
- Full Text
- View/download PDF
38. Solid-phase synthesis and biochemical evaluation of conformationally constrained analogues of deglycobleomycin A5.
- Author
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Cagir A, Tao ZF, Sucheck SJ, and Hecht SM
- Subjects
- Bleomycin chemical synthesis, DNA chemistry, Models, Molecular, Molecular Structure, Oxidation-Reduction, Bleomycin analogs & derivatives, Bleomycin chemistry
- Abstract
Deglycobleomycin binds to and degrades the self-complementary oligonucleotide d(CGCTAGCG)(2) in a sequence selective fashion. A previous modeling study [J. Am. Chem. Soc. 120, (1998), 7450] had shown that, during binding to double stranded DNA, the conformation of the methylvalerate domain of deglycoBLM approximated that of S-proline. In the belief that an analogue of deglycoBLM structurally constrained to mimic the DNA-bound conformation might exhibit facilitated DNA binding and cleavage, an analogue of deglycoBLM was prepared in which the methylvalerate moiety was replaced by S-proline. This deglycoBLM analogue, as well as the related analogue containing R-proline, was synthesized on a TentaGel resin. Both of the analogues were found to be capable of binding Fe(2+) and activating O(2) for transfer to styrene. However, both deglycoBLM analogues exhibited diminished abilities to effect the relaxation of supercoiled plasmid DNA, and neither mediated sequence selective DNA cleavage.
- Published
- 2003
- Full Text
- View/download PDF
39. Conformationally constrained analogues of bleomycin A5.
- Author
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Rishel MJ, Thomas CJ, Tao ZF, Vialas C, Leitheiser CJ, and Hecht SM
- Subjects
- Antibiotics, Antineoplastic chemical synthesis, Antibiotics, Antineoplastic pharmacology, Bleomycin chemical synthesis, Bleomycin pharmacology, DNA drug effects, DNA metabolism, DNA Damage, Molecular Conformation, Oxidation-Reduction, Structure-Activity Relationship, Styrene chemistry, Antibiotics, Antineoplastic chemistry, Bleomycin analogs & derivatives, Bleomycin chemistry
- Abstract
The bleomycin (BLM) group antitumor antibiotics are glycopeptide-derived natural products shown to cause sequence selective lesions in DNA. Prior studies have indicated that the linker region, composed of the methylvalerate and threonine residues, may be responsible for a conformational bend in the agent required for efficient DNA cleavage. We have synthesized a number of conformationally constrained methylvalerate analogues and incorporated them into deglycobleomycin A(5) congeners using our recently reported procedure for the solid phase construction of (deglyco)bleomycin and its analogues. These analogues were designed to probe the effects of conformational constraint of the native valerate moiety. Initial experiments indicated that the constrained molecules, none of which mimic the conformation proposed for the natural valerate linker, possessed DNA cleavage activity, albeit with potencies less than that of (deglyco)BLM and lacking sequence selectivity. Further experiments demonstrated that these analogues failed to produce alkali-labile lesions in DNA or sequence selective oxidative damage in RNA. However, two of the conformationally constrained deglycoBLM analogues were shown to mediate RNA cleavage in the absence of added Fe(2+). The ability of the analogues to mediate the oxygenation of small molecules was also assayed, and it was shown that they were as competent in the transfer of oxygen to low molecular weight substrates as the parent compound.
- Published
- 2003
- Full Text
- View/download PDF
40. Sequence specificity, reactivity, and antitumor activity of DNA-alkylating pyrrole-imidazole diamides.
- Author
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Bando T, Iida H, Tao ZF, Narita A, Fukuda N, Yamori T, and Sugiyama H
- Subjects
- Alkylation, Antineoplastic Agents, Alkylating chemistry, Base Sequence, Cell Line, Tumor, Diamide chemistry, Diamide pharmacology, Drug Screening Assays, Antitumor, Duocarmycins, Gene Expression Profiling, Humans, Imidazoles chemistry, Imidazoles pharmacology, Indoles chemistry, Inhibitory Concentration 50, Molecular Sequence Data, Molecular Structure, Oligonucleotide Array Sequence Analysis, Pyrroles chemistry, Pyrroles pharmacology, Pyrrolidinones chemistry, Antineoplastic Agents, Alkylating pharmacology, DNA metabolism
- Abstract
Three conjugates of imidazole (Im)-pyrrole (Py) diamide and a DNA-alkylating moiety derived from the antibiotic duocarmycin A were synthesized, and their sequence specificity, reactivity, and antitumor activity comparatively examined. Sequencing gel analysis indicated that ImPyDu (1) alkylates DNA at the 3' end of AT-rich sequences at micromolar concentration. ImPyDu86 (2) reacts with DNA at AT-rich sites together with dialkylation sites at micromolar concentration. ImPyLDu86 (3) efficiently alkylates dialkylation sites at nanomolar concentration. Average values of log IC(50) against a 39 cancer cell line panel of 1-3 were -4.59, -5.95, and -8.25, respectively. The differential growth inhibition pattern of 1-3 varied with relatively low correlation coefficients. Array-based gene expression monitoring was performed for 3 in a human lung cancer cell line. Substantial downregulation of expression was seen for genes involved in DNA damage response, transcription, and signal transduction.
- Published
- 2003
- Full Text
- View/download PDF
41. Solid-phase synthesis of bleomycin A(5) and three monosaccharide analogues: exploring the role of the carbohydrate moiety in RNA cleavage.
- Author
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Thomas CJ, Chizhov AO, Leitheiser CJ, Rishel MJ, Konishi K, Tao ZF, and Hecht SM
- Subjects
- Base Sequence, DNA chemistry, DNA metabolism, Molecular Sequence Data, Nucleic Acid Conformation, RNA chemistry, Structure-Activity Relationship, Bleomycin analogs & derivatives, Bleomycin chemical synthesis, Bleomycin pharmacology, Monosaccharides chemistry, Monosaccharides pharmacology, RNA metabolism
- Abstract
The solid-phase synthesis of bleomycin A5 (BLM A5) and three monosaccharide analogues is presented. The monosaccharide analogues incorporated alpha-d-mannose, alpha-l-gulose, and alpha-l-rhamnose moieties in lieu of the disaccharide normally present in BLM A5. Also explored were the abilities of each of the monosaccharide congeners to cleave a 53-nt RNA. The elaboration of these carbohydrate-modified bleomycin analogues helps to define the role of the disaccharide moiety during the RNA cleavage event. The relatively facile solid-phase synthesis of bleomycin A5 and each of the carbohydrate analogues constitutes an important advance in the continuing mechanistic studies of bleomycin.
- Published
- 2002
- Full Text
- View/download PDF
42. Sequence-specific protection of plasmid DNA from restriction endonuclease hydrolysis by pyrrole-imidazole-cyclopropapyrroloindole conjugates.
- Author
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Fujimoto K, Iida H, Kawakami M, Bando T, Tao ZF, and Sugiyama H
- Subjects
- Alkylation, Base Sequence, DNA chemistry, DNA, Superhelical chemistry, DNA, Superhelical metabolism, Deoxyribonucleases, Type II Site-Specific metabolism, Electrophoresis, Polyacrylamide Gel, Plasmids chemistry, Plasmids genetics, Plasmids metabolism, Sequence Analysis, DNA, DNA metabolism, DNA Restriction Enzymes metabolism, Imidazoles chemistry, Pyrroles chemistry
- Abstract
The pyrrole-imidazole (Py-Im) triamide-cyclopropa pyrroloindole (CPI) conjugates ImPyImLDu86 (7) and ImImPyLDu86 (14) were synthesized and their alkylating activities and inhibitory effects on DNA hydrolysis by restriction endonucleases were examined. Sequencing gel analysis demonstrated that conjugates 7 and 14 specifically alkylated DNA at 5'-CGCGCG-3' and 5'-PyGGCCPu-3', respectively. Agarose gel electrophoresis indicated that incubation of a supercoiled plasmid, pSPORT I (4109 bp), with conjugate 7 effectively inhibited its hydrolysis by BssHII (5'-G_CGCGC-3'), whereas conjugate 14 had no effect on this hydrolysis. These results suggest that conjugate 7 sequence-specifically inhibits the hydrolysis of DNA by BssHII. Sequence-specific alkylation by the Py-Im triamide-CPI conjugates was further confirmed by inhibition of the Eco52I (5'-C_GGCCG-3') hydrolysis of conjugate 14-treated pQBI PGK (5387 bp). In clear contrast, hydrolysis of pQB1 PGK by DraI (3'-TTT_AAA-3') was not inhibited by 5 micro M conjugate 14. That ImImPy did not inhibit the hydrolysis of pQB1 PGK indicates that covalent bond formation is necessary for inhibition. A similar experiment, using linear pQBI PGK, achieved the same extent of protection of the DNA with approximately half the concentration of conjugate 14 as was required to protect supercoiled DNA from hydrolysis.
- Published
- 2002
- Full Text
- View/download PDF
43. Solid-phase synthesis of deglycobleomycins: a C-terminal tetraamine linker that permits direct evaluation of resin-bound bleomycins.
- Author
-
Tao ZF, Leitheiser CJ, Smith KL, Hashimoto S, and Hecht SM
- Subjects
- Antibiotics, Antineoplastic chemistry, Antibiotics, Antineoplastic metabolism, Bleomycin metabolism, Ligands, Microscopy, Fluorescence, Resins, Plant chemistry, Antibiotics, Antineoplastic chemical synthesis, Bleomycin analogs & derivatives, Bleomycin chemical synthesis, Bleomycin chemistry, Bridged-Ring Compounds chemistry, DNA chemistry, Resins, Plant metabolism
- Abstract
Deglycobleomycin analogues having different length polyamine side chains at the C-terminus were synthesized using a novel solid-phase synthesis strategy that produces fully deprotected deglycobleomycin congeners attached to the resin. Detailed studies of DNA cleavage by these compounds and their resin-bound counterparts using supercoiled plasmid DNAs and DNA restriction fragments as substrates revealed that (i) the length of the polyamine side chain of free deglycoBLM had limited effect on its DNA cleavage potency or sequence selectivity, and (ii) the nature of the linker moiety between the resin and attached deglycobleomycin had a more substantial effect on the potency of DNA cleavage, but no effect on sequence selectivity of resin-bound deglycoBLMs. Resin-bound 4 exhibited efficient DNA cleavage, indicating that its tetraamine linker moiety could be used for the elaboration and direct evaluation of bleomycin congeners attached to resins.
- Published
- 2002
- Full Text
- View/download PDF
44. Alteration of the selectivity of DNA cleavage by a deglycobleomycin analogue containing a trithiazole moiety.
- Author
-
Thomas CJ, McCormick MM, Vialas C, Tao ZF, Leitheiser CJ, Rishel MJ, Wu X, and Hecht SM
- Subjects
- Antibiotics, Antineoplastic chemistry, Antibiotics, Antineoplastic pharmacology, Bacillus subtilis genetics, Bacillus subtilis metabolism, Base Sequence, Bleomycin pharmacology, DNA, Superhelical metabolism, Molecular Sequence Data, RNA, Transfer, His drug effects, RNA, Transfer, His metabolism, Thiazoles chemistry, Thiazoles pharmacology, Antibiotics, Antineoplastic chemical synthesis, Bleomycin analogs & derivatives, Bleomycin chemical synthesis, Bleomycin chemistry, DNA, Superhelical drug effects, Thiazoles chemical synthesis
- Abstract
The bleomycin (BLM) group of antitumor antibiotics effects DNA cleavage in a sequence-selective manner. Previous studies have indicated that the metal-binding and bithiazole moieties of BLM are both involved in the binding of BLM to DNA. The metal-binding domain is normally the predominant structural element in determining the sequence selectivity of DNA binding, but it has been shown that replacement of the bithiazole moiety with a strong DNA binder can alter the sequence selectivity of DNA binding and cleavage. To further explore the mechanism by which BLM and DNA interact, a trithiazole-containing deglycoBLM analogue was synthesized and tested for its ability to relax supercoiled DNA and cleave linear duplex DNA in a sequence-selective fashion. Also studied was cleavage of a novel RNA substrate. Solid-phase synthesis of the trithiazole deglycoBLM A(5) analogue was achieved using a TentaGel resin containing a Dde linker and elaborated from five key intermediates. The ability of the resulting BLM analogue to relax supercoiled DNA was largely unaffected by introduction of the additional thiazole moiety. Remarkably, while no new sites of DNA cleavage were observed for this analogue, there was a strong preference for cleavage at two 5'-GT-3' sites when a 5'-(32)P end-labeled DNA duplex was used as a substrate. The alteration of sequence selectivity of cleavage was accompanied by some decrease in the potency of DNA cleavage, albeit without a dramatic diminution. In common with BLM, the trithiazole analogue of deglycoBLM A(5) effected both hydrolytic cleavage of RNA in the absence of added metal ion and oxidative cleavage in the presence of Fe(2+) and O(2). In comparison with BLM A(5), the relative efficiencies of hydrolytic cleavage at individual sites were altered.
- Published
- 2002
- Full Text
- View/download PDF
45. Deglycobleomycin: solid-phase synthesis and DNA cleavage by the resin-bound ligand.
- Author
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Smith KL, Tao ZF, Hashimoto S, Leitheiser CJ, Wu X, and Hecht SM
- Subjects
- Antibiotics, Antineoplastic chemistry, Bleomycin chemistry, Electrophoresis, Polyacrylamide Gel, Indicators and Reagents, Ligands, Microscopy, Fluorescence, Resins, Plant, Antibiotics, Antineoplastic chemical synthesis, Bleomycin analogs & derivatives, Bleomycin chemical synthesis, DNA chemistry
- Abstract
[structure: see text] A greatly improved solid-phase synthesis of deglycobleomycin using a Dde-based linker is reported. The resin-bound deglycobleomycin could be completely deblocked and assayed for DNA plasmid relaxation, sequence-selective DNA cleavage, and light production from a molecular beacon.
- Published
- 2002
- Full Text
- View/download PDF
46. Synthesis and DNA cleavage activity of a novel bleomycin A(5) glycoconjugate.
- Author
-
Choudhury AK, Tao ZF, and Hecht SM
- Subjects
- Bleomycin chemistry, Bleomycin pharmacology, Carcinoma, Squamous Cell drug therapy, Catalysis, DNA metabolism, Humans, Liver cytology, Molecular Structure, Structure-Activity Relationship, Tumor Cells, Cultured drug effects, Bleomycin analogs & derivatives, Bleomycin chemical synthesis, DNA drug effects, Plasmids chemistry
- Abstract
[structure in text] To explore the possibility of modifying bleomycin in a fashion that could alter its physiological distribution in a therapeutic setting, a new analogue of bleomycin has been prepared. This analogue is intended to target the asialoglycoprotein receptor on liver cells. Critically, despite the large C-substituent, the bleomycin conjugate was found to degrade DNA in the same fashion as bleomycin A(5) itself, and with only modestly decreased efficiency.
- Published
- 2001
- Full Text
- View/download PDF
47. Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs.
- Author
-
Yang XL, Hubbard RB, Lee M, Tao ZF, Sugiyama H, and Wang AH
- Subjects
- Base Pairing, Base Sequence, Binding Sites, DNA chemistry, DNA genetics, Dimerization, Guanine Nucleotides chemistry, Guanine Nucleotides genetics, Hydrogen Bonding, Imidazoles chemistry, Ligands, Models, Molecular, Nitrogen metabolism, Nuclear Magnetic Resonance, Biomolecular, Protons, Substrate Specificity, Thymine Nucleotides chemistry, Thymine Nucleotides genetics, Titrimetry, Base Pair Mismatch genetics, DNA metabolism, Guanine Nucleotides metabolism, Imidazoles metabolism, Nucleic Acid Conformation, Thymine Nucleotides metabolism
- Abstract
The T:G mismatched base pair is associated with many genetic mutations. Understanding its biological consequences may be aided by studying the structural perturbation of DNA caused by a T:G base pair and by specific probing of the mismatch using small molecular ligands. We have shown previously that AR-1-144, a tri-imidazole (Im-Im-Im) minor groove binder, recognizes the sequence CCGG. NMR structural analysis of the symmetric 2:1 complex of AR-1-144 and GAACCGGTTC revealed that each AR-1-144 binds to four base pairs with the guanine N2 amino group forming a bifurcated hydrogen bond to a side-by-side Im/Im pair. We predicted that the free G-N2 amino group in a T:G wobble base pair can form two individual hydrogen bonds to a side-by-side Im/Im pair. Thus an Im/Im pair may be a good recognition motif for a T:G base pair in DNA. Cooperative and tight binding of an AR-1-144 homodimer to GAACTGGTTC permits a detailed structural analysis by 2D NOE NMR refinement and the refined structure confirms our prediction. Surprisingly, AR-1-144 does not bind to GAATCGGTTC. We further show that both the Im-Im-Im/Im-Py-Im heterodimer and the Im-Im-Im/Im-Im-Im homodimer bind strongly to the CACGGGTC + GACTCGTG duplex. These results together suggest that an Im/Im pair can specifically recognize a single T:G mismatch. Our results may be useful in future design of molecules (e.g. linked dimers) that can recognize a single T:G mismatch with specificity.
- Published
- 1999
- Full Text
- View/download PDF
48. Sequence-specific alkylation of DNA by duocarmycin A and its novel derivatives bearing PY/IM polyamides.
- Author
-
Tao ZF, Fujiwara T, Saito I, and Sugiyama H
- Subjects
- Alkylation, Duocarmycins, Pyrrolidinones chemistry, Alkylating Agents chemistry, DNA chemistry, Indoles, Nylons chemistry
- Abstract
A new class of sequence-specific DNA alkylating agents were developed based on the reactivity of duocarmycin A and the DNA-reading ability of pyrrole-imidazole polyamide. The DNA alkylation sequence specificity by duocarmycin A can be modulated by a variety of pyrrole-imidazole triamides in a predictable manner. Novel hybrids of the segment A of duocarmycin A and pyrrole-imidazole polyamides efficiently and highly selectively alkylated the target base possessing match sequences of Dervan's binding code.
- Published
- 1999
- Full Text
- View/download PDF
49. Sequence-Specific DNA Alkylation by Hybrid Molecules between Segment A of Duocarmycin A and Pyrrole/Imidazole Diamide.
- Author
-
Tao ZF, Fujiwara T, Saito I, and Sugiyama H
- Abstract
In the absence of distamycin A (Dist), hybrids 1 (X=N, CH) selectively alkylate the 3' end of adenine in AT-rich DNA sequences. However, these hybrids can form a heterodimer with Dist to alkylate G residues of predetermined DNA sequences efficiently and with high selectivity., (© 1999 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)
- Published
- 1999
- Full Text
- View/download PDF
50. Synthesis of pyrrole-imidazole-duocarmycin polyamide and its sequence selective DNA alkylation.
- Author
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Fujiwara T, Tao ZF, Saito I, and Sugiyama H
- Subjects
- Alkylation, Dimerization, Distamycins chemistry, Imidazoles chemistry, Indicators and Reagents, Molecular Structure, Pyrroles chemistry, DNA chemistry, Imidazoles chemical synthesis, Pyrroles chemical synthesis
- Abstract
The new solid phase synthesis of sequence-specific DNA alkylating polyamides containing segment A of Du86 (Duo), N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids is described. New monomer building block N-carboxylmethyl Py (Pyc) was synthesized from 2-methylpyrrolecarboxylate by eight steps. After normal coupling of FMOC-protected-Im and -Py monomer, the deprotection of silyl group generates free carboxylic acid. Introduction of various types of functional groups on solid support will be presented.
- Published
- 1999
- Full Text
- View/download PDF
Catalog
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