Integrating amino acids into Bcr-Abl inhibitors: design, synthesis, biological evaluation, and in silico studies.

ABSTRACT: Bcr-Abl is successfully applied to drug discovery as a CML therapeutic target, but point mutation resistance has become a major challenge in the clinical treatment of CML. Our previous studies have shown that the introduction of amino acids as flexible linkers and heterocyclic structures as HBMs can achieve potent inhibition of Bcr-Abl^T315I. In continuation of these studies, we further enriched the linker types by developing a library of compounds with tert-leucine or serine as a linker. Biological results showed that these compounds exhibited enhanced inhibition against Bcr-Abl^WT and Bcr-Abl^T315I kinases as well as improved antiproliferative activity in leukemia cell assays compared to previously disclosed compounds. In particular, compounds TL8, TL

SUBMITTER: Liu Y 

PROVIDER: S-EPMC11376069 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature