High-throughput identification and characterization of novel inhibitors of Regulator of G Protein Signaling 17 as pretherapeutic leads for the treatment of lung and prostate cancers

Ligands for G-protein-coupled receptors (GPCRs) represent approximately 50% of currently marketed drugs. Regulators of G Protein Signaling (RGS) proteins modulate heterotrimeric G proteins and, thus, GPCR signaling, by accelerating the intrinsic GTPase activity of the G subunit. Given the prevalence of GPCR targeted therapeutics and the role RGS proteins play in G protein signaling, some RGS proteins are emerging as targets in their own right. One such RGS protein is RGS17. Increased RGS17 expression in some prostate and lung cancers has been demonstrated to support cancer progression, while reduced expression of RGS17 can lead to development of chemotherapeutic resistance in ovarian cancer. High-throughput screening is a powerful tool for lead compound identification, and utilization of high-throughput technologies has led to the discovery of several RGS inhibitors, thus far. As screening technologies advance, the identification of novel lead compounds and the subsequent development of targeted therapeutics appears promising. Introduction Every cell maintains homeostasis and communicates with the surrounding environment. This often occurs through complex signaling pathways involving specific protein: protein interactions (ppi). These signaling cascades are often initiated by membrane bound receptors. One of the most important classes of these cellular receptors are the GPCRs. GPCRs are delimited by seven trans-membrane helices, an N-terminus extending into the extracellular environment, and a C-terminus in the intracellular milieu. Members of this family include receptors for many hormones, neurotransmitters,