Development of Small Molecule Kinase Degraders as Chemical Biology Probes and Cancer Therapies

Abstract

Advances in chemical biology provide immense benefits to human health through the discovery of new medicines and new scientific tools to study disease. I have contributed to the advancement of this field by developing a number of small molecule degraders useful as chemical biology probes and efficacious for the treatment of leukemias and lymphomas. Nicknamed “chemical CRISPR”, small molecule degrader technology leverages the cell’s own ubiquitin-proteasomal machinery towards the knockdown of therapeutically relevant targets. Here, I present the development of promiscuous degraders and their use as a tool in proteomic screening for degradable kinases. This tool was used to discover Bruton’s Tyrosine Kinase (BTK) as a top degradable hit. I have developed highly potent and selective small molecule degraders of BTK that have efficacy in patient-derived xenograft mouse models of mantle cell lymphoma (MCL), a devastating disease with very few treatments available today. Although the clinically-approved BTK inhibitor ibrutinib has been successful in MCL and a number of other B-cell malignancies, many patients display resistance to the drug. As small molecule-induced degradation has recently shown promise as a novel therapeutic strategy to overcome the limitations of traditional inhibitors, I sought to investigate the therapeutic potential of targeted BTK degradation. Here, I demonstrate that BTK degradation has more potent and durable signaling and anti-proliferative effects on cancer cells than BTK inhibition alone, and that BTK degraders are able to overcome acquired ibrutinib resistance by degrading BTK C481S, a mutant that is not affected by ibrutinib. Moreover, through systematic variation of chemical structure, I generated DD-03-171, an optimized lead compound that exhibits enhanced anti-proliferative effects on MCL and other cancer cells in vitro as well as efficacy in a patient-derived xenograft model of MCL. Thus, I demonstrate that targeted BTK degradation is an effective therapeutic approach to overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.