Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 14, Pages 6002-6017Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00360
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Funding
- U. S. National Institutes of Health
- NIH Director's Pioneer Award [DP1OD006933/DP1CA174419]
- Lustgarten Foundation Research Investigator Grant
- National Cancer Institute SPORE Grant in GI Cancer [5P50A095103-09]
- Vanderbilt Institute of Chemical Biology
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- NIH SIG Grant [1S-10RR025677-01]
- Vanderbilt University
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
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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 (SOSl). 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 pERKl/2(T202/Y204) protein levels at higher compound concentrations.
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