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Aberrant activation of Wnt/β‐catenin signaling causes tumorigenesis and promotes the proliferation of colorectal cancer cells. Porcupine inhibitors, which block secretion of Wnt ligands, may have only limited clinical impact for the treatment of colorectal cancer, because most colorectal cancer is caused by loss‐of‐function mutations of the tumor suppressor adenomatous polyposis coli ( APC ) downstream of Wnt ligands. Tankyrase poly( ADP ‐ribosyl)ates ( PAR ylates) Axin, a negative regulator of β‐catenin. This post‐translational modification causes ubiquitin‐dependent degradation of Axin, resulting in β‐catenin accumulation. Tankyrase inhibitors downregulate β‐catenin and suppress the growth of  APC ‐mutated colorectal cancer cells. Herein, we report a novel tankyrase‐specific inhibitor  RK ‐287107, which inhibits tankyrase‐1 and ‐2 four‐ and eight‐fold more potently, respectively, than G007‐ LK , a tankyrase inhibitor that has been previously reported as effective in mouse xenograft models.  RK ‐287107 causes Axin2 accumulation and downregulates β‐catenin, T‐cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated  APC  mutations. Consistently,  RK ‐287107 inhibits the growth of  APC ‐mutated (β‐catenin‐dependent) colorectal cancer  COLO ‐320 DM  and  SW 403 cells but not the  APC ‐wild (β‐catenin‐independent) colorectal cancer  RKO  cells. Intraperitoneal or oral administration of  RK ‐287107 suppresses  COLO ‐320 DM  tumor growth in  NOD ‐ SCID  mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and   MYC   downregulation. These observations indicate that  RK ‐287107 exerts a proof‐of‐concept antitumor effect, and thus may have potential for tankyrase‐directed molecular cancer therapy.

RK ‐287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model