17 results on '"Jayaraman, Lata"'
Search Results
2. The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer
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Padmakar Darne, Chetan, Velaparthi, Upender, Saulnier, Mark, Frennesson, David, Liu, Peiying, Huang, Audris, Tokarski, John, Fura, Aberra, Spires, Thomas, Newitt, John, Spires, Vanessa M., Obermeier, Mary T., Elzinga, Paul A., Gottardis, Marco M., Jayaraman, Lata, Vite, Gregory D., and Balog, Aaron
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- 2022
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3. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-Beta signaling
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Shi, Yigong, Wang, Yan-Fei, Jayaraman, Lata, Yang, Haijuan, Massague, Joan, and Pavletich, Nikola P.
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Protein binding -- Research ,DNA binding proteins -- Research ,Transforming growth factors -- Research ,Cytokines -- Research ,Biological sciences - Abstract
A new DNA binding motif was revealed when the crystal structure of a Smad3 MH1 domain bound to a DNA sequence was examined using a 2.8 armstrong resolution X-ray. An 11-residue Beta hairpin embedded in the DNA provides the base-specific DNA recognition in the crystals. A surface loop region, where tumorigenic map, was found to be a functional surface that is important for Smad activity.
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- 1998
4. High mobility group protein-1 (HMG-1) is a unique activator of p53
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Jayaraman, Lata, Moorthy, Narayani Chandra, Murthy, Kanneganti G.K., Manley, James L., Bustin, Michael, and Prives, Carol
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DNA binding proteins -- Research ,Genetic transcription -- Regulation ,Biological sciences - Abstract
Binding of p53 protein to DNA is set off by interaction with covalent and noncovalent modifiers. Identification of a factor from HeLa nuclear extracts that start up p53 CNA binding has been achieved. It was found to be a high-mobility group protein, HMG-1, and belongs to a family of much-conserved chromatin-associated nucleoproteins. Members of the family bend DNA and aid binding of some transcription factors to cognate DNA sequences. Recombinant His-tagged HMG-1 helps in p53 DNA binding in vitro and HMG-1; p53 can interact directly in vitro. HMG-1 is unique as an activator of p53.
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- 1998
5. Activation of p53 sequence-specific DNA binding by short single strands of DNA requires the p53 C-terminus
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Jayaraman, Lata and Prives, Carol
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Tumor suppressor genes -- Research ,DNA binding proteins -- Analysis ,Biological sciences - Abstract
Short single stranded DNA nucleotides having 16-40 nucleotides can stimulate the binding of human and murine p53 proteins to a p53 response element in supercoiled DNA but not the binding of a split p53 in which the C-terminal is missing. The p53 tumor suppressor protein which is activated when DNA is damaged, has an activation center, a DNA binding domain and an oligomerization domain. p53 activates many genes when the concentration of DNA damaging agents is high.
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- 1995
6. Activation of p53 sequence-specific DNA bindingby short single strands of DNA requires the p53 C-terminus
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Jayaraman, Lata and Prives, Carol
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Tumor proteins -- Analysis ,Protein binding -- Analysis ,DNA -- Analysis ,Biological sciences - Abstract
Byline: Lata Jayaraman, Carol Prives Abstract: Upon cellular DNA damage, the p53 tumor suppressor protein transmits a signal to genes that control the cell cycle and apoptosis. One function of p53 that is important for its role in this pathway is its ability to function as a sequence-specific transcriptional activator. We demonstrate here that short single DNA strands can markedly stimulate the ability of human and murine p53 proteins to bind specifically to a p53 response element in supercoiled DNA. We also show that single-stranded DNA does not stimulate binding by a truncated p53 that lacks the C-terminal domain. Finally, we establish that a peptide spanning the p53 C-terminus has the ability in trans to stimulate sequence-specific DNA binding by p53 dramatically. These data taken together suggest a model in which the p53 C-terminus can recognize DNA structures resulting from damage-induced lesions, and this interaction can be propagated to regulate positively p53 sequence-specific DNA binding. Author Affiliation: Department of Biological SciencesColumbia University New York, New York 10027, USA
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- 1995
7. Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)
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Huynh, Tram, Chen, Zhong, Pang, Suhong, Geng, Jieping, Bandiera, Tiziano, Bindi, Simona, Vianello, Paola, Roletto, Fulvia, Thieffine, Sandrine, Galvani, Arturo, Vaccaro, Wayne, Poss, Michael A., Trainor, George L., Lorenzi, Matthew V., Gottardis, Marco, Jayaraman, Lata, and Purandare, Ashok V.
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- 2009
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8. Benzo[ d]imidazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)—Hit to Lead studies
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Wan, Honghe, Huynh, Tram, Pang, Suhong, Geng, Jieping, Vaccaro, Wayne, Poss, Michael A., Trainor, George L., Lorenzi, Matthew V., Gottardis, Marco, Jayaraman, Lata, and Purandare, Ashok V.
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- 2009
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9. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1)
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Purandare, Ashok V., Chen, Zhong, Huynh, Tram, Pang, Suhong, Geng, Jieping, Vaccaro, Wayne, Poss, Michael A., Oconnell, Jonathan, Nowak, Kimberly, and Jayaraman, Lata
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- 2008
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10. An electrophoretic mobility shift assay for the identification and kinetic analysis of acetyl transferase inhibitors
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Fanslau, Caroline, Pedicord, Donna, Nagulapalli, Sujatha, Gray, Hillary, Pang, Suhong, Jayaraman, Lata, Lippy, Jonathan, and Blat, Yuval
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BIOLOGICAL assay , *ELECTROPHORESIS , *TRANSFERASES , *CHEMICAL kinetics , *HOMEOSTASIS , *COENZYMES , *HIGH throughput screening (Drug development) - Abstract
Abstract: Histone acetyl transferases are important regulators of cellular homeostasis. This study describes a sensitive acetyl transferase electrophoretic mobility shift assay applicable both for kinetic analysis of acetyl transferase inhibitors and for high-throughput testing. Application of the assay for human GCN5L2 enabled dissection of inhibitor competition with respect to acetyl coenzyme A. Furthermore, we demonstrated that the assay can detect time-dependent inhibition of human GCN5L2 by reactive inhibitors. [Copyright &y& Elsevier]
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- 2010
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11. A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit.
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Kopinja J, Sevilla RS, Levitan D, Dai D, Vanko A, Spooner E, Ware C, Forget R, Hu K, Kral A, Spacciapoli P, Kennan R, Jayaraman L, Pucci V, Perera S, Zhang W, Fischer C, and Lam MH
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- Adult, Animals, Brain drug effects, Brain metabolism, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Female, Gene Expression Profiling, Glioma drug therapy, Glioma genetics, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Mice, Inbred C57BL, Mice, SCID, Mutant Proteins genetics, Mutant Proteins metabolism, Survival Rate, Xenograft Model Antitumor Assays, Brain Neoplasms mortality, Enzyme Inhibitors pharmacology, Glioma mortality, Glutarates metabolism, Isocitrate Dehydrogenase antagonists & inhibitors, Mutant Proteins antagonists & inhibitors, Mutation
- Abstract
Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.
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- 2017
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12. CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α.
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Tian X, Nguyen M, Foote HP, Caster JM, Roche KC, Peters CG, Wu P, Jayaraman L, Garmey EG, Tepper JE, Eliasof S, and Wang AZ
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- Animals, Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Chemoradiotherapy methods, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Nude, Nanoconjugates, Xenograft Model Antitumor Assays, Camptothecin pharmacology, Cyclodextrins pharmacology, DNA Repair drug effects, Hypoxia-Inducible Factor 1, alpha Subunit biosynthesis, Radiation-Sensitizing Agents pharmacology, Rectal Neoplasms pathology
- Abstract
Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)
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- 2017
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13. Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle-Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer.
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Pham E, Yin M, Peters CG, Lee CR, Brown D, Xu P, Man S, Jayaraman L, Rohde E, Chow A, Lazarus D, Eliasof S, Foster FS, and Kerbel RS
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- Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors pharmacology, Animals, Bevacizumab administration & dosage, Bevacizumab pharmacology, Camptothecin administration & dosage, Camptothecin pharmacology, Cell Line, Tumor, Cyclodextrins administration & dosage, Cyclodextrins pharmacology, Female, Humans, Mice, Mice, SCID, Nanoparticles, Triple Negative Breast Neoplasms pathology, Angiogenesis Inhibitors therapeutic use, Bevacizumab therapeutic use, Camptothecin therapeutic use, Cyclodextrins therapeutic use, Triple Negative Breast Neoplasms drug therapy
- Abstract
VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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14. Dissecting Therapeutic Resistance to ERK Inhibition.
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Jha S, Morris EJ, Hruza A, Mansueto MS, Schroeder GK, Arbanas J, McMasters D, Restaino CR, Dayananth P, Black S, Elsen NL, Mannarino A, Cooper A, Fawell S, Zawel L, Jayaraman L, and Samatar AA
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- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Extracellular Signal-Regulated MAP Kinases chemistry, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Regulation, Neoplastic drug effects, Humans, Models, Molecular, Molecular Conformation, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Protein Binding, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Rats, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm genetics, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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15. Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer.
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Huang A, Jayaraman L, Fura A, Vite GD, Trainor GL, Gottardis MM, Spires TE, Spires VM, Rizzo CA, Obermeier MT, Elzinga PA, Todderud G, Fan Y, Newitt JA, Beyer SM, Zhu Y, Warrack BM, Goodenough AK, Tebben AJ, Doweyko AM, Gold DL, and Balog A
- Abstract
Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.
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- 2015
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16. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.
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Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, Dinunzio E, Windsor W, Zhang R, Zhao S, Angagaw MH, Pinheiro EM, Desai J, Xiao L, Shipps G, Hruza A, Wang J, Kelly J, Paliwal S, Gao X, Babu BS, Zhu L, Daublain P, Zhang L, Lutterbach BA, Pelletier MR, Philippar U, Siliphaivanh P, Witter D, Kirschmeier P, Bishop WR, Hicklin D, Gilliland DG, Jayaraman L, Zawel L, Fawell S, and Samatar AA
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- Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm genetics, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, MAP Kinase Kinase Kinases antagonists & inhibitors, Mutation, Neoplasms drug therapy, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Signal Transduction drug effects, Extracellular Signal-Regulated MAP Kinases genetics, MAP Kinase Kinase Kinases genetics, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics
- Abstract
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.
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- 2013
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17. Structural basis for CARM1 inhibition by indole and pyrazole inhibitors.
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Sack JS, Thieffine S, Bandiera T, Fasolini M, Duke GJ, Jayaraman L, Kish KF, Klei HE, Purandare AV, Rosettani P, Troiani S, Xie D, and Bertrand JA
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- Amino Acid Sequence, Catalytic Domain drug effects, Crystallography, X-Ray, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Indoles metabolism, Molecular Sequence Data, Protein Binding drug effects, Protein-Arginine N-Methyltransferases metabolism, Pyrazoles metabolism, Indoles antagonists & inhibitors, Indoles chemistry, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Protein-Arginine N-Methyltransferases chemistry, Pyrazoles antagonists & inhibitors, Pyrazoles chemistry
- Abstract
CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.
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- 2011
- Full Text
- View/download PDF
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