Special Organic Colloquium – Prof. Herman O. Sintim

Novel chemotypes of kinase inhibitors for the potential treatment of recurrent cancers

Abstract: Therapeutic resistance remains a critical issue in cancer treatment. While cancer patients who harbor dysregulated protein kinases benefit from the use of kinase inhibitors (KIs), many fail therapy and almost all patients become resistant to treatment, indicating a critical unmet need to prevent treatment failure. 

Thus far (as of December 2021), the FDA has approved 69 protein kinase inhibitors and several others are also in various stages of clinical trials. Although many compounds that inhibit protein kinases have been described in the literature, only a small region of the chemical space has been explored for protein kinase inhibition and the majority of FDA approved kinase inhibitors contain only a handful of core moieties, such as indazole, quinoline, isoquinoline, quinazoline, pyrazole and pyrimidine. To belabor this point, about ~20% of FDA-approved protein kinases contain the pyrimidine moiety while six drugs contain quinazoline and eight drugs contain pyrazole. In other words, about 50% of approved protein kinase inhibitors contain one of pyrimidine, pyrazole or quinazoline, highlighting the lack of progress in using other regions of the chemical space to drug protein kinases. The Sintim group, integrating computational and experimental workflows, has identified a few novel chemotypes that inhibit disease-associated protein kinases (such as FLT3, RET, CDKs, Haspin) with sub-nanomolar IC50 values. Some of these new KI are long residence time (hours) inhibitors and have shown impressive efficacies in animal models of various cancers. Two of such compounds are currently undergoing toxicology studies to determine safe dosing regimens for potential phase 1 clinical trials against drug-resistant FLT3 (F691L and D835V/Y)-driven AML and RET (solvent front mutations)-driven lung cancers