Discovery of (<i>S</i>)‑1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl‑1<i>H</i>‑pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1<i>H</i>)‑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
10.1021/acs.jmedchem.6b00389.s001
https://acs.figshare.com/articles/journal_contribution/Discovery_of_i_S_i_1-_1-_4-Chloro-3-fluorophenyl_-2-hydroxyethyl_-4-_2-_1-methyl_1_i_H_i_pyrazol-5-yl_amino_pyrimidin-4-yl_pyridin-2_1_i_H_i_one_GDC-0994_an_Extracellular_Signal-Regulated_Kinase_1_2_ERK1_2_Inhibitor_in_Early_Clinical_Development/3422317
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 (<b>22</b>), an orally bioavailable small molecule
inhibitor selective for ERK kinase activity.
2016-05-26 00:00:00
MEK inhibitors
molecule inhibitor
RAF
oncogenic mutations
nod
resistance
RAS
ERK kinase activity
Clinical Development
pathway
GDC
BRAF