Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling

Deregulated RAS activity,
often the result of mutation, is implicated
in approximately 30% of all human cancers. Despite this statistic,
no clinically successful treatment for RAS-driven tumors has yet been
developed. One approach for modulating RAS activity is to target and
affect the activity of proteins that interact with RAS, such as the
guanine nucleotide exchange factor (GEF) son of sevenless homologue
1 (SOS1). Here, we report on structure–activity relationships
(SAR) in an indole series of compounds. Using structure-based design,
we systematically explored substitution patterns on the indole nucleus,
the pendant amino acid moiety, and the linker unit that connects these
two fragments. Best-in-class compounds activate the nucleotide exchange
process at submicromolar concentrations in vitro, increase levels
of active RAS–GTP in HeLa cells, and elicit signaling changes
in the mitogen-activated protein kinase−extracellular regulated
kinase (MAPK–ERK) pathway, resulting in a decrease in pERK1/2T202/Y204 protein levels at higher compound concentrations.