Evaluation of the Selectivity and Cysteine Dependence of Inhibitors across the Regulator of G Protein-Signaling Family

Michael P Hayes; Christopher R Bodle; David L Roman

doi:10.1124/mol.117.109843

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Evaluation of the Selectivity and Cysteine Dependence of Inhibitors across the Regulator of G Protein-Signaling Family

Journal article

Open access

Peer reviewed

Evaluation of the Selectivity and Cysteine Dependence of Inhibitors across the Regulator of G Protein-Signaling Family

Michael P Hayes, Christopher R Bodle and David L Roman

Molecular pharmacology, Vol.93(1), pp.25-35

01/2018

DOI: 10.1124/mol.117.109843

PMCID: PMC5708088

PMID: 29051318

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Abstract

Since their discovery more than 20 years ago, regulators of G protein-signaling (RGS) proteins have received considerable attention as potential drug targets because of their ability to modulate G activity. Efforts to identify small molecules capable of inhibiting the protein-protein interactions between activated G subunits and RGS proteins have yielded a substantial number of inhibitors, especially toward the well studied RGS4. These efforts also determined that many of these small molecules inhibit the protein-protein interactions through covalent modification of cysteine residues within the RGS domain that are located distal to the G -binding interface. As some of these cysteine residues are highly conserved within the RGS family, many of these inhibitors display activity toward multiple RGS family members. In this work, we sought to determine the selectivity of these small-molecule inhibitors against 12 RGS proteins, as well as against the cysteine-null mutants for 10 of these proteins. Using both biochemical and cell-based methods to assess G -RGS complex formation and G enzymatic activity, we found that several previously identified RGS4 inhibitors were active against other RGS members, such as RGS14, with comparable or greater potency. Additionally, for every compound tested, activity was dependent on the presence of cysteine residues. This work defines the selectivity of commercially available RGS inhibitors and provides insight into the RGS family members for which drug discovery efforts may be most likely to succeed.

Amino Acid Sequence

Drug Evaluation, Preclinical - methods

RGS Proteins - genetics

GTP-Binding Proteins - physiology

Protein Structure, Secondary

GTP-Binding Proteins - antagonists & inhibitors

Humans

Rats

Cysteine - chemistry

Thiazolidinediones - chemistry

Cysteine - genetics

Dose-Response Relationship, Drug

Animals

Signal Transduction - drug effects

RGS Proteins - chemistry

Cysteine - pharmacology

Signal Transduction - physiology

RGS Proteins - antagonists & inhibitors

Thiazolidinediones - pharmacology

Details

Title: Subtitle: Evaluation of the Selectivity and Cysteine Dependence of Inhibitors across the Regulator of G Protein-Signaling Family
Creators: Michael P Hayes - Department of Pharmaceutical Sciences and Experimental Therapeutics University of Iowa (M.P.H., C.R.B., D.L.R.) and Cancer Signaling and Experimental Therapeutics Program, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics (D.L.R.), Iowa City, Iowa
Christopher R Bodle - Department of Pharmaceutical Sciences and Experimental Therapeutics University of Iowa (M.P.H., C.R.B., D.L.R.) and Cancer Signaling and Experimental Therapeutics Program, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics (D.L.R.), Iowa City, Iowa
David L Roman - Department of Pharmaceutical Sciences and Experimental Therapeutics University of Iowa (M.P.H., C.R.B., D.L.R.) and Cancer Signaling and Experimental Therapeutics Program, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics (D.L.R.), Iowa City, Iowa david-roman@uiowa.edu
Resource Type: Journal article
Publication Details: Molecular pharmacology, Vol.93(1), pp.25-35
Publisher: United States
DOI: 10.1124/mol.117.109843
PMID: 29051318
PMCID: PMC5708088
ISSN: 0026-895X
eISSN: 1521-0111
Grant note: T32 GM067795 / NIGMS NIH HHS
Language: English
Date published: 01/2018
Academic Unit: Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984065391302771

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