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 p...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-07, Vol.61 (14), p.6002-6017
Main Authors: Abbott, Jason R, Hodges, Timothy R, Daniels, R. Nathan, Patel, Pratiq A, Kennedy, J. Phillip, Howes, Jennifer E, Akan, Denis T, Burns, Michael C, Sai, Jiqing, Sobolik, Tammy, Beesetty, Yugandhar, Lee, Taekyu, Rossanese, Olivia W, Phan, Jason, Waterson, Alex G, Fesik, Stephen W
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
Cell signaling
Drug Design
HeLa Cells
Humans
Indoles
Indoles - chemistry
Indoles - pharmacology
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Models, Molecular
Monomers
Peptides and proteins
Piperidines - chemistry
Protein Conformation
ras Proteins - chemistry
ras Proteins - metabolism
Signal Transduction - drug effects
SOS1 Protein - chemistry
SOS1 Protein - metabolism
Structure activity relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00360