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 (IC 50 50-75 pM), being roughly 100-fold more potent than vinblastine, and that exhibited decreased susceptibility to Pgp effluxderived 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 substoichiometric 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 sub-stoichiometic drugs that inhibit normal microtublin maturation and dynamics.

Inverse Electron Demand Diels–Alder Reactions of Heterocyclic Azadienes, 1-Aza-1,3-Butadienes, Cyclopropenone Ketals, and Related Systems. A Retrospective

“…In the course of these efforts, we comprehensively defined the importance and role of nearly every atom and substituent in vinblastine and vincristine, including the vindoline C4 acetate, C5 ethyl substituent, C6–C7 double bond, and the vindoline core structure itself, and have systematically explored the upper catharanthine-derived C20′ ethyl substituent, C16′ methyl ester, added C10′ or C12′ indole substitutions, and, most recently, the C20′ alcohol . We have shown that the latter is remarkably tolerant to replacement, resulting in the discovery of both ultrapotent analogues of the natural products as well as those that match the potency of the natural products but do not suffer from overexpressed Pgp-derived resistance (Figure ).…”

“…We have shown that the latter is remarkably tolerant to replacement, resulting in the discovery of both ultrapotent analogues of the natural products as well as those that match the potency of the natural products but do not suffer from overexpressed Pgp-derived resistance (Figure ). Because each of three classes of improved analogues that we discovered , not only incorporate added structural features not found in the natural products, but also substantially surpass their properties, we like to think of them as prototypical examples of “supernatural” products…”

Development of Anticancer Drugs: From Mechanical Properties of Tumor Stiffness to Cytoskeleton-Targeting Natural Products

“…Vinblastine is completely opposite to paclitaxel in the anticancer mechanism used as the microtubule-destabilizing drug [54]. This product mainly inhibits the polymerization of tubulin, and hinders the formation of spindle microtubules, so that nuclear fission stops at the middle stage.…”

Sub-stoichiometric Modulation of Viral Targets─Potent Antiviral Agents That Exploit Target Vulnerability

“…There are many examples of targeting the function of eukaryotic proteins with small molecules that reflect stoichiometric ratios of target to drug that range from 2 to 4 . However, higher order oligomeric proteins like tubulin, amyloid β-protein (Aβ), or α-synuclein are susceptible to intervention at modulator concentrations that reflect much greater sub-stoichiometric ratios, as high as 2 million for gold nanoparticles inhibiting the aggregation of Aβ. − This phenomenon represents a powerful example of the concept of target vulnerability that combines practicality and efficacy with high potency …”