Generating Novel Aryl Thiazole Based Inhibitors of TMEM-16A

TMEM-16a is a membrane protein which functions as a calcium activated chlorine channel (CaCC). The protein TMEM16A is encoded by the Anoctamin-1 (ANO1) gene in humans which is calcium dependent. “Oral cancer over expressed 2” is an alternative name for TMEM-16a and if often used in the place of it. Recently, a study on biliary epithelial cells (BEC's) has provided enough information for us to believe that TMEM16A is what controls the channel leading to calcium activated chloride secretion in response to extracellular nucleotides relating to cystic fibrosis, oral cancer, liver disease, and more. Since the molecular identity and structure of these proteins in still unclear, a group of scientists at UCSF, led by Prof. Alan Verkman screened roughly 110,000 compounds and discovered that there were four main classes of molecules that fully inhibited TMEM16A and had an IC50<10uM. We are working on optimizing one class of these molecules, substituted aryl thiazoles, to potentially give us an IC50 value less than 1uM. The central hypothesis of this project is to explore the chemical structure of the aryl thiazole lead inhibitor scaffold, to generate new inhibitors with improved potency. Doing this will allow us to learn more about CaCC's and allow for sufficient disease cures relating to it.