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

Abstract

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.

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2]; ORCiD logo [2]
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  2. Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); Lustgarten Foundation; National Cancer Institute (NCI)
OSTI Identifier:
1544873
Grant/Contract Number:  
1S-10RR025677-01; AC02-06CH11357; DP1OD006933/ DP1CA174419; 5P50A095103−09
Resource Type:
Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 9; Journal Issue: 9; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; RAS; SOS1; nucleotide exchange; structure-based design; quinazolines

Citation Formats

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., and Fesik, Stephen W. Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS. United States: N. p., 2018. Web. doi:10.1021/acsmedchemlett.8b00296.
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. Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS. United States. https://doi.org/10.1021/acsmedchemlett.8b00296
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., and Fesik, Stephen W. Wed . "Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS". United States. https://doi.org/10.1021/acsmedchemlett.8b00296. https://www.osti.gov/servlets/purl/1544873.
@article{osti_1544873,
title = {Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS},
author = {Abbott, Jason R. and Patel, Pratiq A. and Howes, Jennifer E. and Akan, Denis T. and Kennedy, J. Phillip and Burns, Michael C. and Browning, Carrie F. and Sun, Qi and Rossanese, Olivia W. and Phan, Jason and Waterson, Alex G. and Fesik, Stephen W.},
abstractNote = {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.},
doi = {10.1021/acsmedchemlett.8b00296},
journal = {ACS Medicinal Chemistry Letters},
number = 9,
volume = 9,
place = {United States},
year = {Wed Aug 08 00:00:00 EDT 2018},
month = {Wed Aug 08 00:00:00 EDT 2018}
}

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