Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS

Abbott, Jason R.; Patel, Pratiq A.; Howes, Jennifer E.; Akan, Denis T.; Kennedy, J. Phillip; Burns, Michael C.; Browning, Carrie F.; Sun, Qi; Rossanese, Olivia W.; Phan, Jason; Waterson, Alex G.; Fesik, Stephen W.

doi:10.1021/acsmedchemlett.8b00296

Title: Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS

Journal Article · Wed Aug 08 00:00:00 EDT 2018 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.8b00296· OSTI ID:1544873

^[1]; Patel, Pratiq A. ^[1]; Howes, Jennifer E. ^[1]; Akan, Denis T. ^[1]; Kennedy, J. Phillip ^[1]; Burns, Michael C. ^[1]; Browning, Carrie F. ^[1]; Sun, Qi ^[1]; Rossanese, Olivia W. ^[1]; Phan, Jason ^[1]; Waterson, Alex G. ^[2];

^[2]

Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)

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). In this paper, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); Lustgarten Foundation; National Cancer Institute (NCI)

Grant/Contract Number:: 1S-10RR025677-01; AC02-06CH11357; DP1OD006933/ DP1CA174419; 5P50A095103−09

OSTI ID:: 1544873

Journal Information:: ACS Medicinal Chemistry Letters, Vol. 9, Issue 9; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 13 works

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60 APPLIED LIFE SCIENCES
RAS
SOS1
nucleotide exchange
structure-based design
quinazolines

Title: Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS

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