Open AccessDiscovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS
Author(s) -
Jason R. Abbott,
Phenil J. Patel,
Jennifer E. Howes,
Denis T. Akan,
J. Phillip Kennedy,
Michael C. Burns,
Carrie F. Browning,
Qi Sun,
Olivia W. Rossanese,
Jason Phan,
Alex G. Waterson,
Stephen W. Fesik
Publication year - 2018
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.8b00296
Subject(s) - guanine nucleotide exchange factor , mapk/erk pathway , kinase , quinazoline , microbiology and biotechnology , gtp' , signal transduction , protein kinase a , chemistry , biology , biochemistry , enzyme , combinatorial chemistry
Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.