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

Abstract

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.