Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1's low clinical toxicity.

ABSTRACT: KXO1 (tirbanibulin or KX2-391) is as a non-ATP-competitive inhibitor of SRC proto-oncogene nonreceptor tyrosine kinase (SRC) and is being clinically investigated for the management of various cancers and actinic keratosis. Recently, KXO1 has also been shown to strongly inhibit tubulin. Interestingly, unlike conventional tubulin-targeting drugs, KXO1 has exhibited low toxicity in preclinical and clinical studies, but the reason for this remains elusive, as are the KXO1-binding site and other details of the interaction of KXO1 with tubulin. Here, cell-based experiments revealed that KXO1 induces tubulin depolymerization and G₂/M phase cell cycle arrest at low nanomolar concentrations, similar to colchicine, used as a positive control. Results from biochemical experiments, includin

SUBMITTER: Niu L 

PROVIDER: S-EPMC6885616 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature