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:
-
- Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
- 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}
}
Web of Science
Works referenced in this record:
Towards an unified hydrogen-bond theory
journal, September 2000
- Gilli, G.; Gilli, P.
- Journal of Molecular Structure, Vol. 552, Issue 1-3
Approaches to Ras signaling modulation and treatment of Ras-dependent disorders: a patent review (2007 – present)
journal, September 2012
- Sacco, Elena; Spinelli, Michela; Vanoni, Marco
- Expert Opinion on Therapeutic Patents, Vol. 22, Issue 11
Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
journal, November 2010
- Vigil, Dominico; Cherfils, Jacqueline; Rossman, Kent L.
- Nature Reviews Cancer, Vol. 10, Issue 12
Hallmarks of Cancer: The Next Generation
journal, March 2011
- Hanahan, Douglas; Weinberg, Robert A.
- Cell, Vol. 144, Issue 5
RAS oncogenes: weaving a tumorigenic web
journal, October 2011
- Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna
- Nature Reviews Cancer, Vol. 11, Issue 11
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
journal, July 2016
- Ostrem, Jonathan M. L.; Shokat, Kevan M.
- Nature Reviews Drug Discovery, Vol. 15, Issue 11
A Comprehensive Survey of Ras Mutations in Cancer
journal, May 2012
- Prior, I. A.; Lewis, P. D.; Mattos, C.
- Cancer Research, Vol. 72, Issue 10
Recent advances in cancer drug discovery targeting RAS
journal, December 2016
- Wilson, Candice Y.; Tolias, Peter
- Drug Discovery Today, Vol. 21, Issue 12
High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling
journal, May 2018
- Burns, Michael C.; Howes, Jennifer E.; Sun, Qi
- Analytical Biochemistry, Vol. 548
Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success
journal, November 2009
- Lovering, Frank; Bikker, Jack; Humblet, Christine
- Journal of Medicinal Chemistry, Vol. 52, Issue 21
Hydrogen bond models and theories: The dual hydrogen bond model and its consequences
journal, May 2010
- Gilli, Paola; Gilli, Gastone
- Journal of Molecular Structure, Vol. 972, Issue 1-3
Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring
journal, October 2012
- Peterson, Lisa A.
- Chemical Research in Toxicology, Vol. 26, Issue 1
The Hallmarks of Cancer
journal, January 2000
- Hanahan, Douglas; Weinberg, Robert A.
- Cell, Vol. 100, Issue 1
Small Molecule–Mediated Activation of RAS Elicits Biphasic Modulation of Phospho-ERK Levels that Are Regulated through Negative Feedback on SOS1
journal, February 2018
- Howes, Jennifer E.; Akan, Denis T.; Burns, Michael C.
- Molecular Cancer Therapeutics, Vol. 17, Issue 5
Drugging the undruggable RAS: Mission Possible?
journal, October 2014
- Cox, Adrienne D.; Fesik, Stephen W.; Kimmelman, Alec C.
- Nature Reviews Drug Discovery, Vol. 13, Issue 11
Ras history: The saga continues
journal, July 2010
- Cox, Adrienne D.; Der, Channing J.
- Small GTPases, Vol. 1, Issue 1
Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling
journal, June 2018
- Abbott, Jason R.; Hodges, Timothy R.; Daniels, R. Nathan
- Journal of Medicinal Chemistry, Vol. 61, Issue 14
Drugging RAS: Know the enemy
journal, March 2017
- Papke, Bjoern; Der, Channing J.
- Science, Vol. 355, Issue 6330
Improving Prospects for Targeting RAS
journal, November 2015
- Singh, Harshabad; Longo, Dan L.; Chabner, Bruce A.
- Journal of Clinical Oncology, Vol. 33, Issue 31
Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
journal, February 2014
- Burns, Michael C.; Sun, Qi; Daniels, R. Nathan
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 9
Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation
journal, February 2015
- Winter, Jon J. G.; Anderson, Malcolm; Blades, Kevin
- Journal of Medicinal Chemistry, Vol. 58, Issue 5
The Ionic Hydrogen Bond
journal, January 2005
- Meot-Ner (Mautner), Michael
- Chemical Reviews, Vol. 105, Issue 1
Works referencing / citing this record:
Primary Benzylamines by Efficient N-Alkylation of Benzyl Alcohols Using Commercial Ni Catalysts and Easy-to-Handle Ammonia Sources
journal, May 2019
- Liu, Yongzhuang; Afanasenko, Anastasiia; Elangovan, Saravanakumar
- ACS Sustainable Chemistry & Engineering, Vol. 7, Issue 13