6 results on '"Jay Larrow"'
Search Results
2. Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
- Author
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Matthew J. LaMarche, Peter Fekkes, Jorge Garcia Fortanet, Michael Shultz, Denise Grunenfelder, Zhouliang Chen, Gang Liu, Chen Christine Hiu-Tung, Minying Pu, Travis Stams, Pascal D. Fortin, Palermo Mark G, Ping Wang, Samuel B. Ho, Brant Firestone, Matthew J. Meyer, Dyuti Majumdar, Laura R. LaBonte, Francois Lenoir, Rajesh Karki, Nick Keen, Cary Fridrich, Michelle Fodor, Jay Larrow, Sarah Williams, Christopher Towler, Timothy Michael Ramsey, Ji-Hu Zhang, Franco Lombardo, Ying-Nan P. Chen, Zhan Deng, Mitsunori Kato, Zhao B. Kang, Lawrence Blas Perez, Shumei Liu, and William R. Sellers
- Subjects
Male ,Models, Molecular ,0301 basic medicine ,Programmed cell death ,Allosteric modulator ,Protein Conformation ,Allosteric regulation ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Crystallography, X-Ray ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,Allosteric Regulation ,Piperidines ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Chemistry ,Small molecule ,High-Throughput Screening Assays ,Mice, Inbred C57BL ,PTPN11 ,Pyrimidines ,030104 developmental biology ,Biochemistry ,Drug Design ,Pyrazines ,030220 oncology & carcinogenesis ,Heterografts ,Molecular Medicine ,Female ,Allosteric Site ,Neoplasm Transplantation - Abstract
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
- Published
- 2016
3. COUNTERION QUANTIFICATION FOR DISCOVERY CHEMISTRY AND PRE-FORMULATION SALT SCREENING
- Author
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Lipa Shah, Thierry Mann, Penny Wright, Jennifer Bilotta, Joseph Twomey, Jay Larrow, Christina Capacci-Daniel, Melissa S. Grondine, Christopher Towler, Stephanie Kay Dodd, and John Reilly
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chemistry.chemical_classification ,Chromatography ,Clinical Biochemistry ,Ion chromatography ,Pharmaceutical Science ,Salt (chemistry) ,Biochemistry ,Analytical Chemistry ,Column chromatography ,chemistry ,Reagent ,Instrumentation (computer programming) ,Counterion ,Pre formulation - Abstract
A fast method was developed to determine the amount of anions and cations present in discovery samples using a reagent free ion chromatography system. The system separates and quantifies counterions present in novel discovery compounds from an accurately weighed sample of 1 mg. The advantage of using these methods in the discovery phase and early development to accurately characterize salt identity and stoichiometry has been demonstrated. Likewise, a further advantage is the ability to accurately quantify undesirable counterions that may be present due to process related manipulation of material and to quantify salt equivalents for “mixed” salt samples. The instrumentation described also has the ability to utilize a reagent-free automated eluent generation approach which in addition to saving time, eliminates the variability that can occur with manually prepared eluents. Several examples have been collated to highlight the usefulness of this approach within discovery.
- Published
- 2012
4. 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
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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
5. Novel 2,3-Dihydro-1,4-Benzoxazines as Potent and Orally Bioavailable Inhibitors of Tumor-Driven Angiogenesis
- Author
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Shaun Flynn, James Bready, Shawn Harriman, Vinod F. Patel, Zhiyang Zhao, Alexander M. Long, Anthony Polverino, Jean-Christophe Harmange, Michael Morrison, Jay Larrow, Nicholas Doerr, Daniel S. La, Juan Estrada, Thomas DeMelfi, Julie Belzile, Matthew Weiss, Julie Flynn, Yohannes Teffera, Douglas A. Whittington, Russell Graceffa, Philip Roveto, Matthew W. Martin, Angela Coxon, and Ling Wang
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Male ,Models, Molecular ,Vascular Endothelial Growth Factor A ,Angiogenesis ,Injections, Subcutaneous ,Administration, Oral ,Biological Availability ,Mice, Nude ,Angiogenesis Inhibitors ,Crystallography, X-Ray ,Ligands ,Cell Line ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Growth factor receptor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Corneal Neovascularization ,Cell Proliferation ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,Neovascularization, Pathologic ,Chemistry ,Endothelial Cells ,Stereoisomerism ,Kinase insert domain receptor ,Vascular Endothelial Growth Factor Receptor-2 ,Benzoxazines ,Rats ,Endothelial stem cell ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Biochemistry ,Models, Animal ,cardiovascular system ,Cancer research ,Molecular Medicine ,Female ,Human umbilical vein endothelial cell ,Signal transduction - Abstract
Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
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- 2008
6. Corrigendum to 'Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors' [Bioorg. Med. Chem. Lett. 19 (2009) 6307]
- Author
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Stephanie Springer, Yusheng Qu, Min-Hwa Jasmine Lin, Yajing Yang, Jay Larrow, Loren Berry, Kavita Shah, Michael Santostefano, Deborah Choquette, Brian K. Albrecht, Michele Potashman, Isabelle Dussault, Yihong Zhang, Paula Kaplan-Lefko, Yohannes Teffera, Christiane Bode, Satoko Hirai, Roman Shimanovich, Julia Lohman, David Bauer, Steven F. Bellon, Karen Rex, April Chen, Mei Fang, Jean-Christophe Harmange, and Alessandro Boezio
- Subjects
chemistry.chemical_compound ,C-Met ,chemistry ,Series (mathematics) ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry - Published
- 2010
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