The Wnt/β-catenin signaling pathway is critical for colorectal cancer (CRC) development, progression and metastasis. Tankyrase enzymes (TNKS1 and TANKS2), members of the PARP (Poly(ADP-ribose)polymerases) superfamily, PARsylate and target Axin for degradation via ubiquitin-proteasome pathway, leading to accumulation of β-catenin into nucleus. In addition, aberrant YAP/TAZ singling contributes to anticancer drug resistance, but inhibition of TNKS suppresses YAP/TAZ signaling through stabilizing Angiomotin (AMOT). Therefore, inhibition of TNKS has emerged as an attractive strategy for treatment of cancers. To identify potent and selective small molecule inhibitors of TNKS1, a TNKS1-ligand docking was used for computational-based virtual screen of a chemical library containing 1.6 million compounds and 24 virtual hits were further subjected to in vitro evaluation for TNKS1 inhibition. Using an in vitro TNKS1 enzyme assay, we identified a novel pyridine derivative (AZ236106) significantly inhibited TNKS1 enzyme activity in a concentration-dependent manner, but not PARP1/2. Treatment of AZ236106 stabilized Axin, reduced β-catenin in nucleus and downregulated β-catenin target genes in DLD-1 cells harboring adenomatous polyposis coli (APC) mutation. Moreover, we observed that AZ236106 inhibited accumulation of YAP in the nucleus and expression of YAP garget genes. Combination treatment of AZ236106 with either radiation or PLX4032, a BRAF inhibitor, decreased cell proliferation and increased apoptotic cell death in DLD-1 and SK-MEL28 cells, compare to AZ236106, radiation or PLX4032 alone. Our findings suggest that AZ236106 may have therapeutic potential in cancers, and could be further refined for efficacy and safety to develop a lead compound.

Citation Format: Hwani Ryu, Ah-young Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4181. doi:10.1158/1538-7445.AM2017-4181