Identification of novel benzimidazole-based small molecule targeting dual targets Tankyrase and Bcl2 to induce apoptosis in Colon cancer

Abstract

Tankyrase is a crucial protein involved in the regulation of various proteins, among which the Wnt / ß catenin pathway and TERF1 are the main critical pathway proteins. Deregulation of the Wnt / ß catenin pathway has been reported in various cancers. Tankyrase regulates the Wnt / ß catenin pathway by stabilizing AXIN1 and AXIN2 through a proteasomal degradation pathway. Targeting tankyrase is an attractive strategy to target cancer due to the importance of tankyrase in the regulation of TERF1, which is directly involved in the maintenance of telomeric length. Bcl2, another crucial antiapoptotic protein predominantly overexpressed in various cancer types involves cell survival and chemo-resistance. Synthesized compounds have displayed potent antiproliferative activity against various cancer cells specifically HCT116 cells displayed the most sensitivity to compounds with IC50 of 32.9 µM. The compound induces efficient apoptosis which was unveiled by Annexin V / PI double staining in HCT116 cells. Colony formation capabilities were diminished in the compound treatment group which displays the potent antiproliferative activity of the compound against HCT116 cells. In silico studies displayed strong interaction of compound 5d with Tankyrase and Bcl2 with a strong binding score of -6.70 kcal/mol and -6.16 kcal/mol respectively.