Identification and Development of Novel TRKA, FLT3, and Dual Aurora B/CSF-1R Kinase Inhibitors

Abstract

Kinase inhibitors have been one of the most widely studied drug classes over the last 30 years. Due to their extensive roles in nearly all biological processes and implications in tumorigenesis and progression, kinases have become one of the flagships of targeted therapy. Impressive efforts in drug development have led to FDA approval for 39 small molecule kinase inhibitors with many more in clinical trials. Although extensive work has already been completed, there is still room for progress. Many kinases that have been identified as drivers for malignant disease are yet to have any treatment approved for therapeutic use. Further, the biological significance and therapeutic value of multiple emerging targets is still being uncovered. The rise of kinase inhibitors in targeted therapy has also brought on challenges with resistance and relapse in patients. These obstacles have created a demand for developing kinases capable of broad mutant activity as well as revealed opportunities in polypharmacology to strategically target multiple targets to minimize risks of resistance. The work presented here describes the effort towards developing inhibitors for four currently underserved kinase targets: tropomyosin receptor kinase A (TRKA), FMS-like tyrosine kinase 3 (FLT3), Aurora B, and colony stimulating factor 1 receptor (CSF-1R). TrkA kinase is a long sought therapeutic target for both cancer and pain that is yet to have an inhibitor obtain FDA approval. 2017 saw the first approval of a FLT3 inhibitor, midostaurin, however it was not fully optimized for FLT3 activity. Inhibitors capable of maintaining full efficacy across FLT3 drug resistant mutants are still needed. Aurora B is another well studied kinase that lacks approved treatment, and CSF-1R is an emerging immunotherapy target aimed at stimulating anti-tumor macrophage activity. Combined, these two targets are optimal candidates for the development of polypharmacological studies. Heavy emphasis was placed on expediting the drug discovery process for identifying novel inhibitors of these kinase targets. Utilization of computational modeling techniques, kinase directed compound libraries, and efficiency enabling synthetic methodologies sought to progress compounds through the drug discovery pipeline as rapidly as possible. In total, the thesis project herein seeks to identify opportunities to provide improved treatment options and future directions for the field of kinase inhibitor development.