Novel Cancer Therapeutics Targeting Cancer Intrinsic and Extrinsic Pathways
Kinase inhibitor (KI) therapy has revolutionized cancer treatment. Thus far the FDA has approved over 70 protein kinase inhibitors and several others are also in various stages of clinical trials. Therapeutic resistance to KIs however 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.
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 is interested in developing kinase inhibitors that inhibit secondary mutated kinases, which paly important roles in drug resistance (i.e. cancer intrinsic pathways) and/or inhibitors that target kinases that regulate the tumor microenvironment (i.e. cancer extrinsic pathways). Integrating computational and experimental workflows, the Sintim lab has identified novel chemotypes that inhibit disease-associated protein kinases (such as Tak1, FLT3, RET, CDKs, Haspin, HUNK) 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 the potential treatment of drug-resistant FLT3 (F691L and D835V/Y)-driven AML and RET (solvent front mutations)-driven lung cancers.