Novel RGS2-Gaq Interaction Inhibitors Show Anti-Cancer Activity

Abstract ID 91690 Poster Board 278 The protein regulator of G-protein signaling 2 (RGS2) is from a family of approximately 30 proteins that bind to the alpha subunits of G proteins (Ga) and are implicated in many human diseases. RGS2 is overexpressed in the majority of solid breast cancers and metastatic prostate cancers. RGS2 is a potent and selective inhibitor of the Guanine nucleotide-binding protein subunit alpha (Gaq), whose knockdown promotes cancer metastasis. We hypothesized that inhibiting RGS2-Gaq interactions would have anti-metastatic effects. Here and using a structure-based approach, we sought to develop selective RGS2 inhibitors targeting the RGS2-Gaq interaction face to block RGS2-Gaq binding. The structure of the RGS2-Gaq complex was used to develop a pharmacophore model which was subsequently used to search chemical databases to identify potential inhibitors. Retrieved hits were further screened by docking to identify leads with high selectivity and potency towards RGS2. The search resulted in 10 compounds (AJ-1 through AJ-10) that successfully blocked RGS2-Gaq binding in cell-based assays. All 10 compounds inhibited the growth of different cancer cell lines with AJ-10 causing over 80% growth inhibition of the glioblastoma SNB-75 cell line at a concentration of 10 uM. In addition, AJ-3 is shown to preferentially bind RGS2, not Gaq, and it inhibits the migration ability of the invasive prostate cancer cell line LNCaP in wound healing assays. These results show that RGS2 inhibitors have anticancer properties. These inhibitors have the potential to be the first-in-class chemotherapeutic agents targeting metastasis by inhibiting RGS2-Gaq binding. 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 project was supported, in part, by the National Center for Advancing Translational Sciences of the National Institutes of Health under Grant Number UM1TR004548. The content is solely the responsibility of the authors' and does not necessarily represent the official views of the National Institutes of Health.