Abstract 5684: Target tubulin polymerization with novel reverse ABI analogs interacting with the colchicine binding site.

Abstract

Abstract Cancer remains one of the leading causes of mortality worldwide. While current therapies are effective in treating early stage cancers, their efficacy against advanced cancers, especially multidrug-resistant cancers, is limited. Our lab recently reported a set of 2-aryl-4-benzoyl-imidazoles (ABI) derivatives with potent anti-proliferative activity against melanoma and prostate cancer cell lines and xenografts. Further optimization has led to the synthesis of a new series of 4-aryl-2-benzoyl-imidazoles with the aryl group and the benzoyl group reversed as compared to the previous ABI structure. The reverse ABI (RABI) compounds were evaluated for biological activity against 8 cancer cell lines including some which were multidrug-resistant. The in vitro results showed that several RABI compounds had excellent antiproliferative properties with IC50 values in the low namomolar range, comparable to existing tubulin-targeting agents such as paclitaxel, colchicine, or vinblastine, but with the ability to effectively circumvent Pgp-mediated drug resistance. The IC50 of the most active compound 12a was 9 nM. The mechanism of action (MOA) of the RABI compounds was investigated using cell cycle analysis, tubulin polymerization assays and molecular docking studies. These studies showed that their antitumor activity was achieved through inhibition of tubulin polymerization at the colchicine binding site. Our results suggest that the novel RABI compounds may be developed as a promising antitumor agent for advanced cancers. Citation Format: Min Xiao, Sunjoo Ahn, Jianjun Chen, Jin Wang, Duane D. Miller, James T. Dalton, Wei Li. Target tubulin polymerization with novel reverse ABI analogs interacting with the colchicine binding site. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5684. doi:10.1158/1538-7445.AM2013-5684