Abstract B17: Traf2- and NCK-interacting kinase (TNIK) inhibitor down-regulates Wnt signaling pathway in cancer cells

Introduction: Aberrant activation of the Wnt signaling pathway has been implicated as the key driver of carcinogenesis, particularly in colorectal cancers. Because nearly 90% of colorectal cancers carry mutations either APC or β-catenin, downstream signaling molecules of the β-catenin destructive complex are considered as more attractive therapeutic targets in drug discovery research for the treatment of colorectal cancers. Recently, Traf2- and NCK-interacting kinase (TNIK) has been identified as one of components of the T-cell factor-4 (TCF4) transcriptional complex and essential for the expression of Wnt target genes. Knockdown of TNIK gene expression suppressed the transcriptional activity of the Wnt signaling pathway, and decreased in proliferation of colorectal cancer cells. Therefore inhibitors of TNIK may represent a promising therapeutic approach for treating Wnt-signal activated cancers. Previously we reported a thiazol-based TNIK inhibitor, N5355 have single digit nM IC50 value and the compound significantly down-regulated the Wnt target genes such as AXIN2 and cMYC in colorectal cancer cell line, HCT116. Further evaluations of N5355 have been implemented to characterize the effects of TNIK inhibition on cancer cell lines.Methods: To study the effects of N5355 on the Wnt signaling pathway, the expression levels of Wnt target proteins were analyzed by Western blotting using Wnt-signal activated cancer cell lines. The ability of N5355 for blocking of nuclear...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signaling Pathways: Wnt: Poster Presentations - Proffered Abstracts Source Type: research