Signal transduction processes are major targets of drug discovery with G protein-coupled receptors being a primary site of action of many current therapeutic agents. Recent work, however, has shown that signaling pathways are not just linear chains of information but are webs of interacting regulatory molecules in which protein scaffolding, intracellular proximity, and inhibitory control are major determinants of signaling efficacy and specificity. The twenty Regulator of G protein Signaling (RGS) protein family members which inhibit G protein signaling represent a novel site of pharmacologic intervention but: 1) their physiological functions remain incompletely understood and 2) there are no reported small molecule inhibitors of RGS function in cells. The identification of selective RGS inhibitors would provide both: 1) tools for the study of RGS function in cells and in vivo and 2) a starting point for therapeutic drug development. In this proposal, we focus on R7 family RGS proteins (e.g. RGS9 and RGS7). These proteins differ from other RGS proteins in two respects. First, they form an obligate heterodimer with G25. Second, they are relatively selective in acting on G1o rather than on Gi or Gq. RGS9 play a key role in dopamine signaling and reward pathways while RGS7 is highly expressed in hippocampal pyramidal cells where it is poised to modulate learning and memory and neuronal excitability underlying epilepsy. We propose to develop a robust cell-based functional assay for assessing the activity of R7 family RGS proteins (e.g. RGS9 and RGS7). Upon successful implementation of the assay, it will be utilized in high-throughput screening in the MLPCN to identify compounds that selectively inhibit or enhance the activity of RGS7 or RGS9. The ultimate aim of this project is the identification of selective small molecule modulators of RGS action which will provide important chemical tools and accelerate the development of novel therapeutics targeting CNS processes.
Much of commercial drug development currently targets a small subset of the human genome which is considered """"""""druggable"""""""". In the present project, we aim to identify chemicals that act on a new family of genes that play a key role in controlling brain function - the regulators of G protein signaling or RGS. The two RGS proteins which are the focus of this project are RGS9 and RGS7. RGS9 plays a key role in controlling the actions of drugs of abuse while RGS7 appears to be important in epilepsy and learning and memory. By inhibiting or enhancing the function of RGS proteins, our long term goal is to develop novel drugs that will improve therapy of these conditions.
Blazer, Levi L; Storaska, Andrew J; Jutkiewicz, Emily M et al. (2015) Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS Chem Neurosci 6:911-9 |