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

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

doi:10.1021/acs.jmedchem.6b00389

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

J Med Chem. 2016 Jun 23;59(12):5650-60. doi: 10.1021/acs.jmedchem.6b00389. Epub 2016 Jun 7.

Authors

James F Blake¹, Michael Burkard¹, Jocelyn Chan², Huifen Chen², Kang-Jye Chou², Dolores Diaz², Danette A Dudley², John J Gaudino¹, Stephen E Gould², Jonas Grina¹, Thomas Hunsaker², Lichuan Liu², Matthew Martinson¹, David Moreno¹, Lars Mueller², Christine Orr², Patricia Pacheco², Ann Qin², Kevin Rasor¹, Li Ren¹, Kirk Robarge², Sheerin Shahidi-Latham², Jeffrey Stults², Francis Sullivan¹, Weiru Wang², Jianping Yin², Aihe Zhou², Marcia Belvin², Mark Merchant², John Moffat², Jacob B Schwarz²

Affiliations

¹ Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
² Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.

PMID: 27227380
DOI: 10.1021/acs.jmedchem.6b00389

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dogs
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Mice
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 3 / metabolism
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridones
Pyrimidines
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
ravoxertinib