Reference Detail

Ref Type

Journal Article

PMID

(27196752)

Authors

Okada-Iwasaki R, Takahashi Y, Watanabe Y, Ishida H, Saito J, Nakai R, Asai A

Title

The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	7	2016 Jul	1525-34	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
K-756	K-756	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
K-756			Tankyrase Inhibitor 11	K-756 inhibits tankyrase, resulting in decreased Wnt/beta-catenin pathway signaling, and potentially leading to decreased tumor cell growth in combination with other agents (PMID: 27196752).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
APC mutant	colorectal cancer	predicted - sensitive	K-756	Preclinical	Actionable	In a preclinical study, K-756 inhibited Wnt signaling and reduced growth of 2/3 tested APC-mutant colorectal cancer cell lines in culture (PMID: 27196752).	27196752