**Background**
The Wnt/β-catenin signaling pathway plays a critical role in the development and maintenance of various tissues, but its aberrant activation is a hallmark of many malignancies, particularly colorectal cancer. Tankyrases (TNKS1 and TNKS2), members of the poly(ADP-ribose) polymerase (PARP) family, are key regulators of this pathway. By modulating the stability of Axin, tankyrases influence the degradation of β-catenin, thereby controlling the transcription of Wnt target genes. Consequently, the inhibition of tankyrase activity has emerged as a promising therapeutic strategy to suppress tumor growth in APC-mutant colorectal cancers. In this context, we will introduce a selective tankyrase inhibitor – K-756.
**Definition**
K-756 is a direct and selective tankyrase inhibitor that targets both TNKS1 and TNKS2, exhibiting IC50 values of 31 nM and 36 nM, respectively.
**In Vitro and In Vivo Studies**
According to the K-756 description, this compound binds to the induced pocket of TNKS to inhibit its enzyme activity. In terms of isoform selectivity, K-756 inhibits TNKS1 and TNKS2 by 97% and 100% at a concentration of 10 μM, while showing minimal inhibitory activity (less than 13%) against other PARP family members, including PARP1, PARP2, PARP3, PARP6, PARP7, and PARP11. Regarding K-756 in vitro activity, the compound strongly inhibits reporter activity in DLD-1/TCF-Luc cells with an IC50 of 110 nM, though it does not inhibit DLD-1/mtTCF-Luc cells even at 1,000 nM. Furthermore, K-756 inhibits the growth of APC-mutant colorectal cancer cell lines; after 144 hours of treatment, the GI50 values for COLO 320DM and SW403 cells were 780 nM and 270 nM, respectively.
The K-756 in vivo efficacy was evaluated using DLD-1/TCF-Luc cell xenografts in SCID mice. When administered orally once daily for 3 days at doses of 100, 200, and 400 mg/kg, K-756 significantly decreased the expression of FGF20 and reporter activity at doses of 100 mg/kg and above. The expression of LGR5 was significantly reduced at doses of 200 mg/kg and above. Maximum inhibitory activity was achieved at a dose of 400 mg/kg, with Wnt/β-catenin signal inhibition observable after just one day of administration. In conclusion, K-756 is a potent and selective tankyrase inhibitor that effectively suppresses the Wnt/β-catenin pathway in K-756 Cancer research models.
Keywords
K-756, 130017-40-2, K756, K 756, PARP, poly ADP ribose polymerase, Inhibitor, inhibitor, inhibit
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