skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling

Abstract

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). In this paper, 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.

Authors:
 [1];  [1]; ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2]; ORCiD logo [2]
  1. Vanderbilt Univ., Nashville, TN (United States). School of Medicine
  2. Vanderbilt Univ., Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Lustgarten Foundation; National Cancer Institute (NCI); USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1498428
Grant/Contract Number:  
DP1OD006933/DP1CA174419; 5P50A095103-09; 1S-10RR025677-01; AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 14; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Cell signaling; Peptides and proteins; Monomers; Structure activity relationship; Indoles

Citation Formats

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., and Fesik, Stephen W. Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling. United States: N. p., 2018. Web. https://doi.org/10.1021/acs.jmedchem.8b00360.
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. Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling. United States. https://doi.org/10.1021/acs.jmedchem.8b00360
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., and Fesik, Stephen W. Fri . "Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling". United States. https://doi.org/10.1021/acs.jmedchem.8b00360. https://www.osti.gov/servlets/purl/1498428.
@article{osti_1498428,
title = {Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling},
author = {Abbott, Jason R. and Hodges, Timothy R. and Daniels, R. Nathan and Patel, Pratiq A. and Kennedy, J. Phillip and Howes, Jennifer E. and Akan, Denis T. and Burns, Michael C. and Sai, Jiqing and Sobolik, Tammy and Beesetty, Yugandhar and Lee, Taekyu and Rossanese, Olivia W. and Phan, Jason and Waterson, Alex G. and Fesik, Stephen W.},
abstractNote = {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). In this paper, 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.},
doi = {10.1021/acs.jmedchem.8b00360},
journal = {Journal of Medicinal Chemistry},
number = 14,
volume = 61,
place = {United States},
year = {2018},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 8 works
Citation information provided by
Web of Science

Save / Share: