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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Radakovic, Aleksandar^1,2  Boger, Dale L.^1,2 

[1] Scripps Res Inst, Dept Chem, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Skaggs Inst Chem Biol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA

关键词: Vinblastine;    Vinca alkaloids;    Vinblastine analogues;    Tubulin;    Microtubulin;   

DOI  :  10.1016/j.bmcl.2019.03.036

来源: Elsevier

【 摘 要 】

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 responsible for the increased potency and show that the ultra-potent extended C20' ureas retain the mechanistic behavior of vinblastine, display enhanced affinity for tubulin and on-target activity approximately 100-fold both in vitro and in HeLa cells, but do not show evidence of catalytic disassembly of microtubulin. We also use the analogues to show that, in live interphase cells, the effects of the vinblastine class of drugs do not display a catastrophic effect on the microtubule skeleton, but rather a subtler insult to its dynamicity, acting as substoichiometric drugs that inhibit normal microtubulin maturation and dynamics.

【 授权许可】

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