Journal article
In Silico Design of Novel RGS2-G alpha-q Interaction Inhibitors with Anticancer Activity
Journal of chemical information and modeling, Vol.64(20), pp.8052-8062
10/28/2024
DOI: 10.1021/acs.jcim.4c00932
PMID: 39401155
Abstract
Regulators of G-protein signaling (RGS) are a family of approximately 30 proteins that bind to and deactivate the alpha subunits of G-proteins (Gα) by accelerating their GTP hydrolysis rates, which terminates G-protein coupled receptor (GPCR) signaling. Thus, RGS proteins are essential in regulating GPCR signaling, and most members are implicated as critical nodes in human diseases such as hypertension, depression, and others. Regulator of G-protein signaling 2 (RGS2), a member of the R4 family of RGS proteins, is overexpressed in many solid breast cancers, and its levels in prostate cancer significantly correlate with the metastatic stage and poor prognosis. We sought to develop RGS2 inhibitors as potential chemotherapeutic agents utilizing structure-based drug design approaches. Available structures of the RGS2-Gα complex were used to extract a pharmacophore model for searching chemical databases. Docking of identified hits to RGS2 as well as other RGS structures was used to screen the hits for potent and selective RGS2 inhibitors. Whole cell assays showed the top 10 ranking compounds, AJ-1–AJ-10, to inhibit RGS2–Gαq interactions. Differential scanning fluorimetry showed AJ-3 to bind RGS2 but not Gαq. All 10 compounds inhibited the growth of several RGS2 expressing cancers in cell culture assays. In addition, AJ-3 inhibited the migration of LNCaP prostate cancer cells in wound healing assays. This is the first group of RGS2 inhibitors identified by structure-based approaches and that show anticancer activity. These results highlight the potential RGS2 inhibitors have to be a new class of chemotherapeutic agents.
Details
- Title: Subtitle
- In Silico Design of Novel RGS2-G alpha-q Interaction Inhibitors with Anticancer Activity
- Creators
- Adam Bair - Ohio Northern UniversityNatalie Printy - Ohio Northern UniversitySo Hee Choi - Ohio Northern UniversityJoshua Wilkinson - University of IowaJoseph O'Brien - University of IowaBrian Myers - Ohio Northern UniversityDavid Roman - University of IowaTarek M Mahfouz - Ohio Northern University
- Resource Type
- Journal article
- Publication Details
- Journal of chemical information and modeling, Vol.64(20), pp.8052-8062
- Publisher
- AMER CHEMICAL SOC
- DOI
- 10.1021/acs.jcim.4c00932
- PMID
- 39401155
- ISSN
- 1549-9596
- eISSN
- 1549-960X
- Grant note
- National Cancer Institute, Bethesda, MD: P30 CA016058
This research was supported by the Bower, Bennet, and Bennet grant from Raabe College of Pharmacy at Ohio Northern University and a summer research grant from Ohio Northern University. This study was supported in part by grant P30 CA016058, National Cancer Institute, Bethesda, MD, and by The Ohio State University Comprehensive Cancer Center. We thank the Clinical Translational Science Shared Resource at The Ohio State University Comprehensive Cancer Center, Columbus, OH, for the RGS2 expression data and the wound healing assays.
- Language
- English
- Electronic publication date
- 10/14/2024
- Date published
- 10/28/2024
- Academic Unit
- Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984737228502771
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