jm6b00389_si_001.pdf (116.36 kB)

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

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journal contribution
posted on 26.05.2016, 00:00 by 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
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.