Molecular dynamics investigation on the Asciminib resistance mechanism of I502L and V468F mutations in BCR-ABL.

Asciminib, a highly selective non-ATP competitive inhibitor of BCR-ABL, has demonstrated to be a promising drug for patients with chronic myeloid leukemia. It is a pity that two resistant mutations (I502L and V468F) have been found during the clinical trial, which is a challenge for the curative effect of Asciminib. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to investigate the molecular mechanism of Asciminib resistance induced by the two mutants. The obtained results indicate that the mutations have adversely influence on the binding of Asciminib to BCR-ABL, as the nonpolar contributions decline in the two mutants. In addition, I502L mutation causes α-helix I' (αI') to shift away from the helical bundle composed of αE, αF, and αH, making the distance between αI' and Asciminib increased. For V468F mutant, the side chain of Phe468 occupies the bottom of the myristoyl pocket (MP), which drives Asciminib to shift toward the outside of MP. Our results provide the molecular insights of Asciminib resistance mechanism in BCR-ABL mutants, which may help the design of novel inhibitors.