The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase

Abstract

Asciminib is a potent, orally bioavailable, investigational drug that specifically and potently inhibits the tyrosine kinase activity of native ABL1, together with that of the chimeric BCR-ABL1 oncoprotein which causes chronic myeloid leukemia (CML). In contrast to ATP-competitive BCR-ABL1 kinase inhibitors employed to treat CML that target multiple kinases, asciminib binds to the myristate binding pocket on the kinase domains of ABL1 and BCR-ABL1. Hitherto no drugs have been developed whose mechanism of action involves interacting with myristate binding pockets on proteins, and analysis of the structures of such binding sites in proteins other than ABL1/ABL2/BCR-ABL1 strongly suggest that asciminib will not bind to these with high affinity. Accordingly, the drug has no known safety liabilities resulting from any off-target activity, as illustrated by its specificity towards cells expressing BCR-ABL1 and lack of effects on non-kinase targets in biochemical screens. Because asciminib does not bind to the ATP-binding site it maintains substantial activity against kinase domain mutations that impart acquired drug resistance to ATP-competitive drugs. However, in vitro studies in cells have identified BCR-ABL1 mutations that reduce the anti-proliferative activity of asciminib, some of which are associated with clinical resistance towards the drug in patients. Here we review effects of asciminib on mutant forms of BCR-ABL1, analyse their sensitivity towards the drug from a structural perspective and affirm support for employing combinations with ATP-competitive inhibitors to impede the reactivation of BCR-ABL1 kinase activity in patients receiving monotherapy.