| References: |
NCB-0846 is novel,first-in-class,orally TNIK inhibitor with an IC50 value of 21 nM,that have shown strong anti-tumor efficacy against several cancer models.NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. NCB-0846 inhibits cancer cell growth in vitro and in vivo.NCB-0846 induced faster migration of TCF4 phosphorylated by TNIK within a concentration range of 0.1–0.3 μM and completely inhibited the phosphorylation of TCF4 at a concentration of 3 μM . Furthermore, NCB-0846 blocked the auto-phosphorylation of TNIK). NCB-0846 inhibited the TCF/LEF transcriptional activity of Wnt3a-treated HEK293 and HCT116 (carrying CTNNB1 mutation) and DLD-1 (carrying APC mutation) colorectal cancer cells. NCB-0846 reduced the expression of the Wnt target genes AXIN2 and MYC as well as that of TNIK, but the expression of CCND1 was not affected .NCB-0846 also reduced the expression of TNIK, AXIN2 and cMYC at the protein level. NCB-0846 showed 6.8-fold higher cell growth-inhibitory activity against HCT116 cells than NCB-0970. Meanwhile, compared with NCB-0970, NCB-0846 showed much higher (~20-fold) inhibitory activity against colony formation by the same cells in soft agar , indicating that this compound has more potent activity against the clonogenicity of cancer cells. NCB-0846 was administrable orally and suppressed the growth of tumours established by inoculating HCT116 cells into immunodeficient mice. The body weight of mice fell at the beginning of NCB-0846 administration, but gradually recovered. |
