Abstract 1350: Novel ABI analogs target the colchicine site in tubulin and overcome multidrug resistance in metastatic melanoma

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL With rapidly rising incidences of metastatic melanoma and its high resistance to current therapeutic agents, developing more effective drugs is urgently needed. We recently discovered a novel class of 2-aryl-4-benzoyl-imidazoles (ABI) analogs. These compounds showed great antiproliferative activity on melanoma cells and the IC50 is as low as 8 nM. ABIs showed equal potency against multidrug resistant melanoma cells and the sensitive parent cells, suggesting that they can effectively overcome P-gp meditated multidrug resistance. ABIs inhibited capillary network formation which indicates high potential for anti-angiogenesis. Cell cycle analysis showed ABIs arrested cells in the G2/M phase and inhibited tubulin polymerization. ABIs bind to the colchicine binding site in the α/β-tubulin heterodimer as indicated by a number of evidences including competitive binding and molecular modeling studies. Immunofluorescence experiments revealed that microtubule modality was dramatically changed with ABIs treatment. In vivo studies using both B16-F1/C57BL model and A375/SHO model showed significant inhibition of melanoma tumor growth by ABIs. These novel analogs hold great promise as new selective agents for the improved treatment of malignant melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1350. doi:10.1158/1538-7445.AM2011-1350