Abstract 4848: Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma

Abstract

Abstract We previously discovered a novel 2-aryl-4-benzoyl-imidazole (ABI) scaffold exerts its potent anti-proliferative effects through interacting with the colchicine binding site in tubulin. Extensive structure-activity relationship (SAR) studies of this novel scaffold showed that the best analog in this series, ABI-231, has an average IC50 = 5.2 nM against panels of melanoma and prostate cancer cell lines, is orally bioavailable, and strongly suppress melanoma tumors in vivo. Analyses of the potential binding pose of ABI-231 at the colchicine binding pocket suggested small substitutions to the indole moiety in ABI-231 could further increase its interactions to tubulin. Based this hypothesis, we have established an efficient synthetic method for the synthesis of ABI-231 analogs by either rotating the indole ring or introducing substituents on the indole of ABI-231. Using this method, we synthesized and tested 27 analogs of ABI-231. Several of the compounds show excellent potency against a panel of melanoma cancer cell lines with a diverse genomic background (mutations in BRAF, TP53, CDKN2A and PTEN) that are frequently encountered in clinical metastatic melanoma tumors. Additionally, they are not substrates for the P-glycoprotein (Pgp) efflux pump and therefore strongly inhibited the multidrug resistant cell lines. The potency of the compounds was further verified by their potent growth inhibition of cancer cell colonies. Results from cell cycle analysis, apoptosis evaluation and tubulin polymerization inhibition are consistent with their expected mechanisms of action. Potential off-target analyses performed by Eurofins Cerep-Panlabs SafetyScreen 44 indicated that they are clean and does not inihibt any of the tested off-targets at 100 fold of its IC50 value in melanoma cells, suggesting the good safety profile for this compound and the probably these scaffold in general. We are currently performing in vivo efficacy studies for the most potent analogs. These compounds hold great promise as a new generation of orally available tubulin inhibitors. Citation Format: Wang Qinghui, Arnst E. Kinsie, Duane D. Miller, Wei Li. Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4848.