A Potent and Selective MasterKey Inhibitor of a Range of Allosteric EGFR/HER2 Mutations
BDTX-189 is designed to be an orally available, irreversible small molecule inhibitor that targets undrugged oncogenic driver mutations of the EGFR and HER2 kinases.
The receptor tyrosine kinases EGFR/HER2 are subject to alterations including ATP site classical mutations and amplification that drive oncogenic activity. Non-canonical EGFR/HER2 mutations, including extracellular domain mutations of HER2, as well as EGFR and HER2 kinase domain exon 20 insertions, and additional activating oncogenic drivers of EGFR/HER2 are found in one to two percent of a large variety of solid tumors and are overexpressed in tumors such as advanced NSCLC, invasive breast, bladder and endometrial cancer, where incidence ranges from two to seven percent. Currently available EGFR and HER2 tyrosine kinase inhibitors or monoclonal antibodies have limited anti-tumor activity against these genetic alterations due lack of selectivity, which results in toxicity and tolerability challenges. There remains a significant unmet medical need for new drugs that can extend targeted therapies to patients expressing non-canonical mutations outside of the ATP site.