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Start Over Author "K A Latham" Journal journal of medicinal chemistry
2 results on '"K A Latham"'

1. Discovery of Highly Potent, Selective, and Efficacious Small Molecule Inhibitors of ERK1/2

Author

Michael Burkard, Andrew T. Metcalf, Kristina West, Stephen E. Gould, Matthew Martinson, John Moffat, Kevin Rasor, Weiru Wang, Li Ren, Jacob Schwarz, Sheerin K. Shahidi-Latham, Patricia Pacheco, Huifen Chen, Jianping Yin, Jonas Grina, David A. Moreno, Rustam Ferdinand Garrey, James F. Blake, John Gaudino, and Brian Dean

Subjects
Models, Molecular, Drug, Pyridones, media_common.quotation_subject, Molecular Conformation, Administration, Oral, Antineoplastic Agents, Pharmacology, Crystallography, X-Ray, Molecular conformation, Small Molecule Libraries, Mice, Structure-Activity Relationship, Mouse xenograft, In vivo, Drug Discovery, Animals, Structure–activity relationship, Tumor growth, Protein Kinase Inhibitors, Cell Proliferation, media_common, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Dose-Response Relationship, Drug, Drug discovery, Chemistry, Xenograft Model Antitumor Assays, Small molecule, Rats, Disease Models, Animal, Molecular Medicine
Abstract

Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.

Published
2015
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2. Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

Author

John Moffat, Marcia Belvin, Lichuan Liu, Jocelyn Chan, Li Ren, Kirk Robarge, Francis J. Sullivan, Jeffrey Stults, Jonas Grina, David A. Moreno, Ann Qin, Matthew Martinson, Stephen E. Gould, Jacob Schwarz, Kang-Jye Chou, Sheerin K. Shahidi-Latham, Lars Mueller, John Gaudino, Aihe Zhou, James F. Blake, Weiru Wang, Danette Dudley, Christine Orr, Michael Burkard, Thomas Hunsaker, Dolores Diaz, Mark Merchant, Huifen Chen, Jianping Yin, Patricia Pacheco, and Kevin Rasor

Subjects
0301 basic medicine, MAPK/ERK pathway, Pyridones, Extracellular signal-regulated kinases, Erk signaling, Antineoplastic Agents, 03 medical and health sciences, Mice, Structure-Activity Relationship, 0302 clinical medicine, Acquired resistance, Dogs, Oncogenic signaling, Drug Discovery, Extracellular, Animals, Humans, Protein Kinase Inhibitors, Cell Proliferation, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Dose-Response Relationship, Drug, Molecular Structure, Kinase, Chemistry, Neoplasms, Experimental, HCT116 Cells, Small molecule, Rats, 030104 developmental biology, Pyrimidines, Biochemistry, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Drug Screening Assays, Antitumor
Abstract

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.

Published
2016

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