title: The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase.
abstract: The Wnt/β-catenin pathway is a well-known oncogenic pathway. Its suppression has long been considered as an important challenge in treating cancer patients. Among colon cancer patients in particular, most patients carry an adenomatous polyposis coli (APC) mutation that leads to an aberration of Wnt/β-catenin pathway. To discover the small molecule inhibitors of the Wnt/β-catenin pathway, we conducted high-throughput screening in APC-mutant colon cancer DLD-1 cells using a transcriptional reporter assay, which identified a selective Wnt/β-catenin pathway inhibitor, K-756. K-756 stabilizes Axin and reduces active β-catenin, and inhibits the genes downstream of endogenous Wnt/β-catenin. We subsequently identified that K-756 is a tankyrase (TNKS) inhibitor. TNKS, which belongs to the PARP family, poly-ADP ribosylates Axin and promotes Axin degradation via the proteasome pathway. K-756 binds to the induced pocket of TNKS and inhibits its enzyme activity. Moreover, PARP family enzyme assays showed that K-756 is a selective TNKS inhibitor. K-756 inhibited the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/β-catenin pathway. An in vivo study showed that the oral administration of K-756 inhibited the Wnt/β-catenin pathway in colon cancer xenografts in mice. To further explore the therapeutic potential of K-756, we also evaluated the effects of K-756 in non-small cell lung cancer cells. Although a single treatment of K-756 did not induce antiproliferative activity, when K-756 was combined with an EGFR inhibitor (gefitinib), it showed a strong synergistic effect. Therefore, K-756, a novel selective TNKS inhibitor, could be a leading compound in the development of anticancer agents. Mol Cancer Ther; 15(7); 1525-34. ©2016 AACR.
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Okada-Iwasaki
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishida
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Saito
authors.affiliation: R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. ryuichiro.nakai@kyowa-kirin.co.jp.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Nakai
authors.affiliation: Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D060466:Axin Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D017491:Genes, APC; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D009154:Mutation; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D059467:Transcriptome; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D060466:Axin Protein; C495270:CTNNB1 protein, human; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051176:beta Catenin; D038501:Tankyrases