Discovery of 1‑(1H‑Pyrazolo[4,3‑c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers
journal contribution
posted on 2016-06-22, 00:00 authored by Jongwon Lim, Elizabeth
H. Kelley, Joey L. Methot, Hua Zhou, Alessia Petrocchi, Hongmin Chen, Susan
E. Hill, Marlene C. Hinton, Alan Hruza, Joon O. Jung, John K. F. Maclean, My Mansueto, George
N. Naumov, Ulrike Philippar, Shruti Raut, Peter Spacciapoli, Dongyu Sun, Phieng SiliphaivanhThe ERK/MAPK pathway
plays a central role in the regulation of
critical cellular processes and is activated in more than 30% of human
cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy
in patients for the treatment of BRAF-mutant melanoma. However, the
majority of responses are transient, and resistance is often associated
with pathway reactivation of the ERK signal pathway. Acquired resistance
to these agents has led to greater interest in ERK, a downstream target
of the MAPK pathway. De novo design efforts of a novel scaffold derived
from SCH772984 by employing hydrogen bond interactions specific for
ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential
SAR studies led to the identification of highly potent and selective
ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression
in the BRAFV600E xenograft model.
