Benzodiazepinone-derived Inhibitors of EGFR and HER2

A class of benzodiazepinone-derived molecules, inhibitors of both triple mutant EGFR and HER2, for cancer therapeutics or biochemical research tools.

Background:

Inhibition of epithelial growth factor receptor (EGFR) as a non-small cell lung cancer (NSCLC) therapeutic is not a new concept, but 75% of patients die within five years of diagnosis. As tumors spread, they develop mutations in the EGFR tyrosine kinase domain, rendering them unsusceptible to standard care. Pharmaceutical companies are presently chasing therapies for triple-mutant EGFR cancers, which have 3 mutations (L858R/T790M/C797S) that are resistant to the current 3^rd generation kinase inhibitors serving as front-line treatment for NSCLC patients.

Technology Overview:

This University at Buffalo invention provides unique chemical structures designed for enhanced binding to EGFR triple-mutant NSCLC, as well as human epithelial growth factor 2 (HER2), providing enhanced selectivity over current commercial treatments. Using fragment-based drug design, bivalent inhibitors were developed that exhibit a wide range of biochemical IC₅₀ values based on differences in the linker that bridges the allosteric and orthosteric sites. These molecules effectively inhibit ATP-binding and serve as therapeutic options for patients with non-small cell lung cancer or HER2 positive breast cancer harboring drug-sensitive mutations in the EGFR kinase domain. Alternatively, these molecules offer a novel option for research on cell signaling or cell proliferation mechanism determinations.

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Advantages:

Novel chemical composition of molecules
Unique bivalent inhibition of both the orthosteric and allosteric sites of kinase inhibitors
Extensive binding within the EGFR allosteric site allows for enhanced selectivity
Inhibits EGFR and HER2
Active on triple mutant strains of EGFR

Applications: