生物活性

• 靶点	TNIK IC50:21nM

• 描述Wnt signaling plays important roles in carcinogenesis and embryonic development. TNIK is a serine/threonine kinase that functions as an activator of the Wnt signaling pathway. TNIK is recruited to promoters of Wnt target genes and required to activate their expression. TCF4 is a substrate of the TNIK enzyme. TNIK phosphorylates TCF4 and regulates its transcriptional activity. TNIK together with NEDD4 and RAP2A form a signaling complex which regulates neuronal dendrite extension and arborization during development. TNIK may also play a role in cytoskeletal rearrangements and regulate cell spreading. NCB-0846 is a TNIK inhibitor. The inhibitory IC₅₀ of NCB-0846 against TNIK kinase was 21 nM. In an experiment system of recombinant TCF4 and TNIK proteins, 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 autophosphorylation of TNIK in hct116 cells. At the concentrations of 3 μM or 10 μM, NCB-0846 reduced the expression of the Wnt target genes AXIN2 and MYC as well as that of TNIK in hct116 cells. NCB-0846 also reduced the expression of TNIK, AXIN2 and cMYC at the protein level at the concentration range of 1 – 10 μM in hct116 and DLD-1 cells. According to another report, NCB-0846 at the concentrations of 1 μM or 3 μM reduced colony formation of cells derived from patients of prostate cancer. In a hct116 xenograft model established in balb/c nude mice, NCB-0846 was administrated to the mice orally at the doses of 40 mg/kg or 80 mg/kg bid. Both doses of NCB-0846 suppressed tumor growth. In a Wnt-driven tumorigenesis model utilizing Apc^min/+ mice, 3 doses of NCB-0846, including 22.5 mg/kg, 45 mg/kg, 90 mg/kg were administrated. NCB-0846 dose dependently reduced the multiplicity and dimensions of tumours that developed in the small intestine of mice.

• 动物研究
  剂量	BALB/c nude mice: 40 mg/kg, 80 mg/kg[2] (p.o., BID)
  给药途径	p.o.