Curtis Thorne, PhD

Arizona Center for Drug Discovery Core Team Member
Assistant Professor, Cellular and Molecular Medicine
Assistant Professor, BIO5 Institute
Member, University of Arizona Cancer Center
Member, Steele Children's Research Center

Research Summary: Discovery and characterization of GSK-3 activators as anti-cancer compounds

Small molecule inhibition of kinase activity is well established as a fruitful therapeutic strategy in oncology. Yet, almost completely neglected is the development of small molecule kinase activators for rationally selected targets. The protein kinase GSK-3 is an outstanding candidate for small molecule activation due to its many allosteric pockets, its central role in tumorogenesis, and its inactivation in numerous cancers. Our work suggests that intestinal cancers may be exquisitely sensitive to GSK-3 activators and that activating GSK-3 would sensitize cancer cells to other therapies. Our research plan is to discover first-in-class GSK-3 activators by screening compound libraries with a biochemical kinase assay followed by complex organoid-based secondary screen. Utilizing a new high-dimensional structure-activity relationship (HD-SAR) approach we have developed, we will categorize the lead compounds into regulators of 3 major processes; 1) proliferation, 2) metabolism, and 3) cytoskeleton. From this drug discovery project, we will characterize small molecules that selectively target and activate GSK-3, useful for testing its function in various physiological and pathophysiological settings. To our knowledge, this proposal represents the first to directly attempt the discovery of “kinase activators”, thus it is high-risk with a potential high-reward. With successful proof-of-principle, we envision kinase activators targeting many of the ~500 known protein kinases becoming a major therapeutic strategy pursued academically and industry-wide. We propose to discover a new class of anti-cancer therapeutic, GSK-3 activators, and demonstrate their efficacy toward intestinal cancers (second deadliest cancer in the western world), thereby establishing an immediate and significant therapeutic utility for lead compounds arising from this project.

Thorne Lab: http://thornelab.org/