Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations.

ABSTRACT: The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-ident

SUBMITTER: Hauser K 

PROVIDER: S-EPMC6110136 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature