12 results on '"Deborah Choquette"'
Search Results
2. Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors
- Author
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Christiane M, Bode, Alessandro A, Boezio, Brian K, Albrecht, Steven F, Bellon, Loren, Berry, Martin A, Broome, Deborah, Choquette, Isabelle, Dussault, Richard T, Lewis, Min-Hwa Jasmine, Lin, Karen, Rex, Douglas A, Whittington, Yajing, Yang, and Jean-Christophe, Harmange
- Subjects
Male ,Models, Molecular ,Pyridones ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Crystallography, X-Ray ,Biochemistry ,Rats, Sprague-Dawley ,Mice ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,Molecular Biology ,Hepatocyte Growth Factor ,Organic Chemistry ,Proto-Oncogene Proteins c-met ,Triazoles ,Rats ,Microsomes, Liver ,Quinolines ,Molecular Medicine ,Signal Transduction - Abstract
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
- Published
- 2012
3. VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia
- Author
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Diane M. Boucher, George Huang, Edward D. Ball, Guanjing Chen, David K. Heidary, Mark N. Namchuk, Jianguo Ma, Yung-Mae Yao, Jinwang Xu, Ron Grey, Forster Cornelia J, Greg Henkel, Jie-Hua Zhou, Michael J. Arnost, Robert J. Davies, and Deborah Choquette
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Male ,Serum ,Cell Survival ,Morpholines ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Receptor tyrosine kinase ,Mice ,Myelogenous ,fluids and secretions ,hemic and lymphatic diseases ,Precursor cell ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,CD135 ,Receptor ,IC50 ,chemistry.chemical_classification ,Mice, Inbred BALB C ,biology ,hemic and immune systems ,Triazoles ,medicine.disease ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Leukemia ,Enzyme ,fms-Like Tyrosine Kinase 3 ,chemistry ,embryonic structures ,biology.protein ,Molecular Medicine ,Neoplasm Transplantation - Abstract
In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.
- Published
- 2012
4. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models
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Martin A. Broome, Jean-Christophe Harmange, Jodi Moriguchi, Hue T. Kha, Benny Amore, Michael A. Damore, Robert Radinsky, Richard Kendall, Teresa L. Burgess, Angela Coxon, Deborah Choquette, Karen Rex, Yihong Zhang, Daniel M. Baker, Jonathan Werner, Paul E. Hughes, Yajing Yang, Isabelle Dussault, Paula Kaplan-Lefko, and Sean Caenepeel
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Cell Survival ,MAP Kinase Signaling System ,Antineoplastic Agents ,Pharmacology ,03 medical and health sciences ,Mice ,Necrosis ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Receptor ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Dose-Response Relationship, Drug ,Kinase ,Chemistry ,Gene Amplification ,Proto-Oncogene Proteins c-met ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Mechanism of action ,Cell culture ,030220 oncology & carcinogenesis ,Phosphorylation ,Female ,medicine.symptom ,Signal Transduction - Abstract
The MET receptor tyrosine kinase is involved in cell growth, survival, and invasion. Clinical studies with small molecule MET inhibitors have shown the role of biomarkers in identifying patients most likely to benefit from MET-targeted therapy. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. Herein, we describe AMG 337 preclinical activity and mechanism of action in MET-dependent tumor models. These studies suggest MET is the only therapeutic target for AMG 337. In an unbiased tumor cell line proliferation screen (260 cell lines), a closely related analogue of AMG 337, Compound 5, exhibited activity in 2 of 260 cell lines; both were MET-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying MET copy numbers revealed that high-level focal MET amplification (>12 copies) was required to confer MET oncogene addiction and AMG 337 sensitivity. One MET-amplified cell line, H1573 (>12 copies), was AMG 337 insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive MET-amplified cell lines demonstrated that AMG 337 inhibited MET and adaptor protein Gab-1 phosphorylation, subsequently blocking the downstream PI3K and MAPK pathways. AMG 337 exhibited potency in pharmacodynamic assays evaluating MET signaling in tumor xenograft models; >90% inhibition of Gab-1 phosphorylation was observed at 0.75 mg/kg. These findings describe the preclinical activity and mechanism of action of AMG 337 in MET-dependent tumor models and indicate its potential as a novel therapeutic for the treatment of MET-dependent tumors. Mol Cancer Ther; 15(7); 1568–79. ©2016 AACR.
- Published
- 2015
5. Bioactivation of Isothiazoles: Minimizing the Risk of Potential Toxicity in Drug Discovery
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Min-Hwa Jasmine Lin, Zhiyang Zhao, Jingzhou Liu, L. Steven Hollis, Adria E. Colletti, Yohannes Teffera, and Deborah Choquette
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Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Metabolite ,Drug Evaluation, Preclinical ,Molecular Conformation ,Pyrazole ,Toxicology ,Mice ,chemistry.chemical_compound ,Dogs ,Cytochrome P-450 Enzyme System ,Risk Factors ,In vivo ,Animals ,Humans ,Naphthyridines ,Chromatography, High Pressure Liquid ,Isothiazole ,biology ,CYP3A4 ,Cytochrome P450 ,General Medicine ,Glutathione ,Rats ,Pyridazines ,Thiazoles ,chemistry ,Biochemistry ,Microsomes, Liver ,Microsome ,biology.protein ,Protein Binding - Abstract
Compound 1, (7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine) is a potent, selective inhibitor of c-Met (mesenchymal-epithelial transition factor), a receptor tyrosine kinase that is often deregulated in cancer. Compound 1 displayed desirable pharmacokinetic properties in multiple preclinical species. Glutathione trapping studies in liver microsomes resulted in the NADPH-dependent formation of a glutathione conjugate. Compound 1 also exhibited very high in vitro NADPH-dependent covalent binding to microsomal proteins. Species differences in covalent binding were observed, with the highest binding in rats, mice, and monkeys (1100-1300 pmol/mg/h), followed by dogs (400 pmol/mg/h) and humans (144 pmol/mg/h). This covalent binding to protein was abolished by coincubation with glutathione. Together, these in vitro data suggest that covalent binding and glutathione conjugation proceed via bioactivation to a chemically reactive intermediate. The cytochrome (CYP) P450 enzymes responsible for this bioactivation were identified as cytochrome P450 3A4, 1A2, and 2D6 in human and cytochrome P450 2A2, 3A1, and 3A2 in rats. The glutathione metabolite was detected in the bile of rats and mice, thus demonstrating bioactivation occurring in vivo. Efforts to elucidate the structure of the glutathione adduct led to the isolation and characterization of the metabolite by NMR and mass spectrometry. The analytical data confirmed conclusively that the glutathione conjugation was on the 4-C position of the isothiazole ring. Such P450-mediated bioactivation of an isothiazole or thiazole group has not been previously reported. We propose a mechanism of bioactivation via sulfur oxidation followed by glutathione attack at the 4-position with subsequent loss of water resulting in the formation of the glutathione conjugate. Efforts to reduce bioactivation without compromising potency and pharmacokinetics were undertaken in order to minimize the potential risk of toxicity. Because of the exemplary pharmacokinetic/pharmacodynamic (PK/PD) properties of the isothiazole group, initial attempts were focused on introducing alternative metabolic soft spots into the molecule. These efforts resulted in the discovery of 7-(2-methoxyethoxy)-N-((6-(3-methyl-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (compound 2), with the major metabolic transformation occurring on the naphthyridine ring alkoxy substituent. However, a glutathione conjugate of compound 2 was produced in vitro and in vivo in a manner similar to that observed for compound 1. Furthermore, the covalent binding was high across species (360, 300, 529, 208, and 98 pmol/mg/h in rats, mice, dogs, monkeys, and humans, respectively), but coincubation with glutathione reduced the extent of covalent binding. The second viable alternative in reducing bioactivation involved replacing the isothiazole ring with bioisosteric heterocycles. Replacement of the isothiazole ring with an isoxazole or a pyrazole reduced the bioactivation while retaining the desirable PK/PD characteristics of compounds 1 and 2.
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- 2010
6. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors
- Author
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Alessandro A, Boezio, Loren, Berry, Brian K, Albrecht, David, Bauer, Steven F, Bellon, Christiane, Bode, April, Chen, Deborah, Choquette, Isabelle, Dussault, Mei, Fang, Satoko, Hirai, Paula, Kaplan-Lefko, Jay F, Larrow, Min-Hwa Jasmine, Lin, Julia, Lohman, Michele H, Potashman, Yusheng, Qu, Karen, Rex, Michael, Santostefano, Kavita, Shah, Roman, Shimanovich, Stephanie K, Springer, Yohannes, Teffera, Yajing, Yang, Yihong, Zhang, and Jean-Christophe, Harmange
- Subjects
C-Met ,Cell Survival ,Clinical Biochemistry ,Mice, Nude ,Neovascularization, Physiologic ,Pharmaceutical Science ,Angiogenesis Inhibitors ,Apoptosis ,Biochemistry ,Receptor tyrosine kinase ,Mice ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Phosphorylation ,Kinase activity ,Protein Kinase Inhibitors ,Molecular Biology ,biology ,Chemistry ,Drug discovery ,Organic Chemistry ,Proto-Oncogene Proteins c-met ,Xenograft Model Antitumor Assays ,Small molecule ,biology.protein ,Molecular Medicine ,Signal transduction ,Tyrosine kinase - Abstract
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.
- Published
- 2009
7. Discovery and Optimization of Triazolopyridazines as Potent and Selective Inhibitors of the c-Met Kinase
- Author
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Steven F. Bellon, Monica Reese, Jay Larrow, Isabelle Dussault, Stephanie Springer, Paula Kaplan-Lefko, Jodi Moriguchi, David Bauer, Yajing Yang, Kavita Shah, Loren Berry, Jean-Christophe Harmange, Christiane Bode, Karen Rex, Brian K. Albrecht, Yihong Zhang, Doug Hoffman, Jasmine Lin, Deborah Choquette, Alessandro Boezio, Alexander M. Long, Roman Shimanovich, Anne B. O’Connor, Aaron C. Siegmund, April Chen, Cary Fridrich, Julia Lohman, Yohannes Teffera, Michele Potashman, and Satoko Hirai
- Subjects
Models, Molecular ,C-Met ,In Vitro Techniques ,Crystallography, X-Ray ,medicine.disease_cause ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Growth factor receptor ,Drug Discovery ,medicine ,Animals ,Phosphorylation ,Molecular Structure ,Oncogene ,Hepatocyte Growth Factor ,Chemistry ,Kinase ,Proto-Oncogene Proteins c-met ,Triazoles ,Rats ,Pyridazines ,Biochemistry ,Microsomes, Liver ,Cancer research ,Molecular Medicine ,Hepatocyte growth factor ,Signal transduction ,Carcinogenesis ,medicine.drug - Abstract
Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
- Published
- 2008
8. Evaluation of a Series of Naphthamides as Potent, Orally Active Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitors
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Virginia Berry, Alexander M. Long, Tom DeMelfi, Nicholas Doerr, Philip Roveto, Yohannes Teffera, Loren Berry, Anthony Polverino, Danlin Chen, Juan Estrada, George Borg, Roger Zanon, Charlie Starnes, James Bready, Shawn Harriman, Kelly Regal, Michael Schrag, Jean-Christophe Harmange, David Bauer, Russell Graceffa, Daniel S. La, Vinod F. Patel, Sesha Neervannan, Matthew Weiss, Angela Coxon, Andrew Tasker, Douglas A. Whittington, Michele Potashman, Julie Flynn, Stephen Kaufman, and Deborah Choquette
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Male ,Models, Molecular ,medicine.medical_specialty ,Angiogenesis ,Drug Evaluation, Preclinical ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Naphthalenes ,Pharmacology ,Crystallography, X-Ray ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Corneal Neovascularization ,Tyrosine ,Protein Kinase Inhibitors ,Cell Proliferation ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Kinase ,Endothelial Cells ,Reproducibility of Results ,Stereoisomerism ,Kinase insert domain receptor ,Vascular Endothelial Growth Factor Receptor-2 ,Rats ,Vascular endothelial growth factor ,Endocrinology ,chemistry ,Enzyme inhibitor ,Drug Design ,Injections, Intravenous ,Microsomes, Liver ,biology.protein ,Molecular Medicine ,Female ,Signal transduction ,Tyrosine kinase - Abstract
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
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- 2008
9. Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors
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Christiane Boezio, Michele Potashman, Yohannes Teffera, Brian K. Albrecht, Julia Lohman, Karina R. Vaida, Alessandro Boezio, Emily A. Peterson, Steven F. Bellon, Deborah Choquette, David Bauer, Katrina W. Copeland, Isabelle Dussault, Roman Shimanovich, Min-Hwa Jasmine Lin, Martin A. Broome, Richard T. Lewis, Jean-Christophe Harmange, Karen Rex, Douglas A. Whittington, and Jingzhou Liu
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Male ,Models, Molecular ,C-Met ,Metabolite ,Pharmacology ,Metastasis ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Drug Discovery ,medicine ,Animals ,Humans ,Tissue Distribution ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,Molecular Structure ,Drug discovery ,Hepatocyte Growth Factor ,Prostatic Neoplasms ,Proto-Oncogene Proteins c-met ,Triazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,Rats ,chemistry ,Protein kinase domain ,Drug Design ,Cancer research ,Microsomes, Liver ,Quinolines ,Molecular Medicine ,Hepatocyte growth factor ,Signal transduction ,medicine.drug ,Signal Transduction - Abstract
The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
- Published
- 2015
10. Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors
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Alan C. Cheng, Ti Cai, Barbara Grubinska, Daniel S. La, Tammy L. Bush, Yohannes Teffera, Joseph L. Kim, Christiane Boezio, Michele Potashman, Russell Graceffa, Erin L. Mullady, Paul S. Andrews, James R. Coats, Katrina W. Copeland, Alessandro Boezio, Emily A. Peterson, Richard T. Lewis, John Stellwagen, Jingzhou Liu, Deborah Choquette, Karina Romero, Adria E. Colletti, Shuyan Yi, Mary K. Stanton, Paul L. Shaffer, and Michelle DuPont
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Male ,Cell signaling ,Imidazopyridine ,Pyridines ,Clinical Biochemistry ,Regulator ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Binding, Competitive ,Rats, Sprague-Dawley ,Mice ,Phosphatidylinositol 3-Kinases ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Structure–activity relationship ,Animals ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,Binding Sites ,Chemistry ,TOR Serine-Threonine Kinases ,Organic Chemistry ,Imidazoles ,Protein Structure, Tertiary ,Pyridazines ,Drug Design ,Microsomes, Liver ,Molecular Medicine ,Benzimidazoles ,Signal transduction ,Half-Life ,Signal Transduction - Abstract
mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.
- Published
- 2012
11. Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia
- Author
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Cameron Stuver-Moody, David K. Heidary, Deborah Choquette, Greg Henkel, Jinwang Xu, Guanjing Chen, Shi-Kai Tian, Forster Cornelia J, Ron Grey, Joanne Ma, Albert C. Pierce, Michael J. Arnost, Mark N. Namchuk, Robert J. Davies, and Vincent Galullo
- Subjects
Models, Molecular ,Morpholines ,Administration, Oral ,Stem cell factor ,Antineoplastic Agents ,Pharmacology ,Rats, Sprague-Dawley ,Myelogenous ,Mice ,Structure-Activity Relationship ,fluids and secretions ,hemic and lymphatic diseases ,Cell Line, Tumor ,Drug Discovery ,medicine ,Potency ,Structure–activity relationship ,Animals ,Humans ,Receptor ,Mice, Inbred BALB C ,Chemistry ,hemic and immune systems ,Hydrogen Bonding ,Triazoles ,medicine.disease ,Rats ,Leukemia ,Leukemia, Myeloid, Acute ,Macaca fascicularis ,Proto-Oncogene Proteins c-kit ,fms-Like Tyrosine Kinase 3 ,Drug Design ,embryonic structures ,Fms-Like Tyrosine Kinase 3 ,Injections, Intravenous ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Protein Binding - Abstract
A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N(3)-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.
- Published
- 2011
12. Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation
- Author
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Matthew W. Martin, Ryan White, Daniel S. La, Matthew Weiss, Anthony Polverino, Andrew Tasker, Lucian DiPietro, Sesha Neervannan, Stephen Kaufman, Roger Zanon, Deborah Choquette, Jean-Christophe Harmange, Juan Estrada, Ling Wang, Kelly Regal, Michele Potashman, Danlin Chen, Tom DeMelfi, Angela Coxon, Nicholas Doerr, Vinod F. Patel, Russell Graceffa, Douglas A. Whittington, Julie Flynn, Shawn Harriman, Alexander M. Long, Charlie Starnes, George Borg, Michael Schrag, Julie Germain, Philip Roveto, Yohannes Teffera, and James Bready
- Subjects
Male ,Models, Molecular ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmacology ,Crystallography, X-Ray ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Drug Discovery ,Cytotoxicity ,Receptor ,Mice, Inbred BALB C ,biology ,Molecular Structure ,Stereoisomerism ,Protein-Tyrosine Kinases ,Vascular endothelial growth factor ,Enzyme inhibitor ,Injections, Intravenous ,Microsomes, Liver ,Molecular Medicine ,Human umbilical vein endothelial cell ,Female ,Signal transduction ,Tyrosine kinase ,medicine.medical_specialty ,Mice, Nude ,Antineoplastic Agents ,Naphthalenes ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Corneal Neovascularization ,Protein Kinase Inhibitors ,Cell Proliferation ,Dose-Response Relationship, Drug ,Endothelial Cells ,Reproducibility of Results ,Rats ,Endocrinology ,Receptors, Vascular Endothelial Growth Factor ,chemistry ,Cell culture ,Drug Design ,biology.protein - Abstract
A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure–activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure–activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
- Published
- 2008
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