Teng Yaxin, Wu Rui, Bo Weichen, Tang Minghai, Wang TaiJin, Cui Xue, Li Yong, Zhang Chufeng, Ma Ziyan, Fu Zhiyuan, Xu Qing, Liu Jie, Chen Lijuan
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Chengdu Zenitar Biomedical Technology Co., Ltd, Chengdu, 610041, China.
Eur J Med Chem. 2024 Mar 15;268:116240. doi: 10.1016/j.ejmech.2024.116240. Epub 2024 Feb 24.
Traf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/β-catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/β-catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1H-imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening. Among them, 35b exhibited excellent TNIK kinase and HCT116 cell inhibitory activity with IC values of 6 nM and 2.11 μM, respectively. 35b also shown excellent kinase selectivity, PK profiles, and oral bioavailability (84.64%). At a p. o. dosage of 50 mg/kg twice daily 35b suppressed tumor growth on the HCT116 xenograft model. Taken together, 35b is a promising lead compound of TNIK inhibitors, which merits further investigation.
肿瘤坏死因子受体相关因子2与Nck相互作用蛋白激酶（TNIK）在调节Wnt/β-连环蛋白信号通路的信号转导中起重要作用，被认为是治疗结直肠癌的重要靶点。抑制TNIK有可能阻断由结直肠癌突变引起的异常Wnt/β-连环蛋白信号转导。我们通过深度片段生长和虚拟筛选发现了一系列6-（1-甲基-1H-咪唑-5-基）喹啉衍生物作为TNIK抑制剂。其中，35b表现出优异的TNIK激酶抑制活性和HCT116细胞抑制活性，IC值分别为6 nM和2.11 μM。35b还表现出优异的激酶选择性、药代动力学特征和口服生物利用度（84.64%）。在每天两次50 mg/kg的口服剂量下，35b抑制了HCT116异种移植模型上的肿瘤生长。综上所述，35b是一种有前景的TNIK抑制剂先导化合物，值得进一步研究。
