Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures

Christopher R Bodle; Josephine H Schamp; Joseph B O'Brien; Michael P Hayes; Meng Wu; Jonathan A Doorn; David L Roman

doi:10.1177/2472555217752301

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Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures

Journal article

Open access

Peer reviewed

Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures

Christopher R Bodle, Josephine H Schamp, Joseph B O'Brien, Michael P Hayes, Meng Wu, Jonathan A Doorn and David L Roman

SLAS discovery, Vol.23(4), pp.363-374

04/2018

DOI: 10.1177/2472555217752301

PMCID: PMC6342279

PMID: 29351497

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Abstract

Regulator of G protein signaling (RGS) proteins temporally regulate heterotrimeric G protein signaling cascades elicited by G protein-coupled receptor activation and thus are essential for cell homeostasis. The dysregulation of RGS protein expression has been linked to several pathologies, spurring discovery efforts to identify small-molecule inhibitors of these proteins. Presented here are the results of a high-throughput screening (HTS) campaign targeting RGS17, an RGS protein reported to be inappropriately upregulated in several cancers. A screen of over 60,000 small molecules led to the identification of five hit compounds that inhibit the RGS17-Gα protein-protein interaction. Chemical and biochemical characterization demonstrated that three of these hits inhibited the interaction through the decomposition of parent compound into reactive products under normal chemical library storage/usage conditions. Compound substructures susceptible to decomposition are reported and the decomposition process characterized, adding to the armamentarium of tools available to the screening field, allowing for the conservation of resources in follow-up efforts and more efficient identification of potentially decomposed compounds. Finally, analogues of one hit compound were tested, and the results establish the first ever structure-activity relationship (SAR) profile for a small-molecule inhibitor of RGS17.

Lung Neoplasms - genetics

Lung Neoplasms - drug therapy

Oncogenes - genetics

RGS Proteins - genetics

Small Molecule Libraries - pharmacology

Protein Interaction Maps - drug effects

Humans

Male

Heterotrimeric GTP-Binding Proteins - genetics

Prostatic Neoplasms - genetics

Signal Transduction - drug effects

Oncogenes - drug effects

Antineoplastic Agents - pharmacology

RGS Proteins - antagonists & inhibitors

Receptors, G-Protein-Coupled - genetics

Prostatic Neoplasms - drug therapy

High-Throughput Screening Assays - methods

Details

Title: Subtitle: Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures
Creators: Christopher R Bodle - 1 Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA, USA
Josephine H Schamp - 1 Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA, USA
Joseph B O'Brien - 1 Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA, USA
Michael P Hayes - 1 Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA, USA
Meng Wu - 3 Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Jonathan A Doorn - 1 Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA, USA
David L Roman - 4 Cancer Signaling and Experimental Therapeutics Program, Holden Comprehensive Cancer Center, UIHC, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: SLAS discovery, Vol.23(4), pp.363-374
Publisher: United States
DOI: 10.1177/2472555217752301
PMID: 29351497
PMCID: PMC6342279
ISSN: 2472-5552
eISSN: 2472-5560
Grant note: R01 CA160470 / NCI NIH HHS P30 ES005605 / NIEHS NIH HHS T32 GM008365 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 04/2018
Academic Unit: Neurology; Pharmacy; Core Research Facilities; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
Record Identifier: 9984065382802771

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