Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Bioorg Med Chem Lett. 2022 Jul 1;67:128745. doi: 10.1016/j.bmcl.2022.128745. Epub 2022 Apr 18.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancer types and Traf2- and Nck-interacting kinase (TNIK) has been thought as a potential target for CRC treatment. Herein we report the discovery and structure-activity relationship (SAR) of benzo[d]oxazol-2(3H)-one derivatives as a new class of TNIK inhibitors. The most potent compound 8g showed an IC value of 0.050 μM against TNIK. It effectively suppressed proliferation and migration of colorectal cancer cells. Western blot analysis indicated that 8g could inhibit aberrant transcription activation of Wnt signaling. Collectively, this study provides a potential lead compound for subsequent drug discovery targeting TNIK.
结直肠癌（CRC）是最常见的癌症类型之一，Traf2 和 Nck 相互作用激酶（TNIK）已被认为是 CRC 治疗的潜在靶点。本文报道了苯并[d]恶唑-2（3H）-酮衍生物作为一类新型 TNIK 抑制剂的发现和构效关系（SAR）。最有效的化合物 8g 对 TNIK 的 IC 值为 0.050 μM。它能有效抑制结直肠癌细胞的增殖和迁移。Western blot 分析表明，8g 可以抑制 Wnt 信号的异常转录激活。总之，这项研究为靶向 TNIK 的后续药物发现提供了一个潜在的先导化合物。
