537.18 - Small molecule inhibitors of human RGS2 developed by structure based drug design approach

Sunday, April 3, 2022

10:57 AM – 11:00 AM

Room: ASPET Poster Discussion Area, Exhibit Hall Booth #1418 - Pennsylvania Convention Center

Introduction: Experience the daily ASPET datablitz, a rapid-fire oral presentation of research. Ten poster presenters each day will present three minute short talks in the ASPET poster discussion lounge in the poster hall (Aisle 1400). These brief snippets of research are an introduction to their full presentations that will take place at their poster boards afterwards. You won’t want to miss this fast-paced overview of the most exciting science of the day.

Natalie Printy (Ohio Northern University), Adam Bair (Ohio Northern University), So-Hee Choi (Ohio Northern University), Joseph OBrien (University of Iowa), Joshua Wilkinson (University of Iowa), David Roman (University of Iowa), David Kinder (Ohio Northern University), Tarek Mahfouz (Ohio Northern University)

Presenting Author(s)

Natalie Printy

Presenting Author
Ohio Northern University

Regulators of G-protein signaling (RGS) is a family of approximately 30 proteins that bind to the alpha subunits of G-proteins (Galpha) and accelerate their GTP hydrolysis rates. This deactivates the G-protein and terminates G-Protein Coupled Receptors (GPCRs) signaling. RGS proteins, therefore, play important roles in regulating GPCR signaling and most members are implicated in human diseases such as hypertension, depression, and others. Regulator of G-protein Signaling 2 (RGS2) is a regulator of angiotensin-II receptor signaling and a modulator of oxytocin receptor signaling as well. More importantly, RGS2 was reported to be over expressed in the majority of solid breast cancers and in metastatic prostate cancer. For this reason, we sought to develop RGS2 inhibitors as potential chemotherapeutic agents. We utilized structure-based drug design approaches to develop inhibitors of RGS2-Galpha-q interactions. Available structures of the RGS2-Galpha complex were used to extract a pharmacophore model for searching of commercially available chemical databases. The identified hits were docked to different RGS structures to screen for compounds with the highest binding potential and most selectivity towards RGS2. We report the first group of inhibitors of RGS2-Galpha-q interactions developed through rational drug design that interfered with RGS2 signaling in cell-based assays. In addition, inhibitor AJ-3 inhibited the growth of MCF-7 breast cancer cells in cell culture assays, which suggests that RGS2 inhibitors may have a potential to be a new class of chemotherapeutic agents.

This research was supported by a Bower Bennet and Bennet research grant from the Raabe College of Pharmacy, Ohio Northern University.