Computationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia.

ABSTRACT: The permeability glycoprotein, encoded by the ABCB1 gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16

SUBMITTER: Hill J 

PROVIDER: S-EPMC11472320 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature