Although microtubule have achieved great success in the last decades and was among the most prolific therapeutic targets for developing anticancer drugs, however, the clinical efficacy of these drugs is often limited by the multidrug resistance that is acquired over the course of treatment, and additional research efforts are urgently demanded to address this shortcoming. We have previously reported 2-aryl-4-benzoylimidazole (ABI) scaffolds including ABI-I, II and III showing highly potent antiproliferative effects both in vitro and in vivo by interacting with colchicine binding site in tubulin. Importantly, these ABI compounds were able to circumvent multidrug resistant mechanisms. As the most potent analog in these series, ABI-231 had an average IC50 value of 5.2 nM against panels of melanoma and prostate cancer cell lines. Molecular modeling studies revealed the existence of unoccupied pockets in the vicinity of the indole moiety that might potentially serve as an opportunity to strengthen the ligand-protein interaction. With the hypothesis in mind, we developed a new synthetic method that was amicable to introduce indole rotation as well as versatile functional groups on the indole moiety. Of these 27 analogs, the 4-methyl-3-indolyl analog showed significantly improved antiproliferative activity in contrast to ABI-231 and its strong inhibitory effect was confirmed through a clonogenic assay. New analogs shared the same mechanism of action as ABI-231 as demonstrated from confocal microscopy, tubulin polymerization assay as well as x-ray crystal structures in complex with tubulin. Wound healing migration assays indicated that the new analogs may potentially induce antimetastatic action through the inhibition of cancer cell motility and migration. Additionally, in vitro metabolism studies revealed that our new analogs possess favorable metabolic and chemical properties. Currently, in vivo efficacy is being evaluated for the best analogs.

Targeting the colchicine binding site in tubulin for cancer treatment: Structural optimization of ABI-231 leads to improved potency and microsomal stability

253rd National Meeting (2017)

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