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
journal contribution
posted on 2016-05-26, 00:00 authored 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. SchwarzThe 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.