Non-ATP competitive kinase inhibitors continue to be investigated due to their ability to exhibit exceptional kinase selectivity, their ability to be combined with ATP-site inhibitors and their ability to exhibit orthogonal resistance profiles. This talk will describe two allosteric drug discovery stories focused on targeting Bcr-Abl for the treatment of Chronic Myelogenous Leukemia (CML) and EGFR for the treatment of EGFR mutant Non-small Cell Lung Cancer (NSCLC). The first story will describe the discovery and identification of myristate-site targeting allosteric Bcr-Abl inhibitors and describe the evolution from GNF-2/GNF-5 to ABL001 (Asciminib). The second story will describe the discovery of the first allosteric EGFR inhibitor EAI045 and the evolution to JBJ-04-125-02 which show promise to inhibit the C797S/L858R EGFR Osimertinib-resistant patient population and the potential to be combined with Osimertinib to suppress the emergence of resistance.

Discovery and development of allosteric inhibitors of Bcr-Abl and EGFR kinases

ACS Spring Meeting 2021

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