Ultra-potent vinblastine analogues improve on-target activity of the parent microtubulin-targeting compound.

ABSTRACT: In recent efforts, several C20' urea vinblastine analogues were discovered that displayed remarkable potency against vinblastine-sensitive tumor cell lines (IC₅₀ 50-75 pM), being roughly 100-fold more potent than vinblastine, and that exhibited decreased susceptibility to Pgp efflux-derived resistance in a vinblastine-resistant cell line. Their extraordinary activity indicate that it is not likely or even possible that their cellular functional activity is derived from stoichiometric occupancy of the intracellular tubulin binding sites. Rather, their potency indicates sub-stoichiometric or even catalytic occupancy of candidate binding sites may be sufficient to disrupt tubulin dynamics or microtubule assembly during mitosis. We detail efforts to delineate the underlying behavior

SUBMITTER: Radakovic A 

PROVIDER: S-EPMC6487230 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature