Discovery of 3,4-Dihydrobenzo[f][1,4]oxazepin-5(2H)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects,Journal of Medicinal Chemistry

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Discovery of 3,4-Dihydrobenzo[f][1,4]oxazepin-5(2H)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-05 , DOI: 10.1021/acs.jmedchem.1c00672
Yueshan Li ₁ , Liting Zhang ₁ , Ruicheng Yang ₁ , Zeen Qiao ₁ , Ming Wu ₁ , Chong Huang ₁ , Chenyu Tian ₂ , Xinling Luo ₂ , Wei Yang ₁ , Yun Zhang ₁ , Linli Li ₂ , Shengyong Yang ₁

Affiliation

The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/β-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/β-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a new class of TNIK inhibitors. Structure–activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound 21k being the most active one (IC₅₀: 0.026 ± 0.008 μM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound 21k could efficiently suppress CRC cell proliferation and migration in in vitro assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, 21k could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.

中文翻译：

3,4-二氢苯并[f][1,4]oxazepin-5(2H)-one衍生物作为一类新型选择性TNIK抑制剂的发现及其抗结直肠癌作用的评估

Traf2 和 Nck 相互作用蛋白激酶 (TNIK) 是 Wnt/β-catenin 通路的下游信号蛋白，被认为是治疗结直肠癌 (CRC) 的潜在靶点，结直肠癌通常与Wnt/β-连环蛋白信号通路。在此，我们报告发现了一系列 3,4-二氢苯并[ f ][1,4]oxazepin-5(2 H )-one 衍生物作为一类新型 TNIK 抑制剂。构效关系 (SAR) 分析鉴定出许多有效的 TNIK 抑制剂，其中化合物21k是最活跃的一种 (IC ₅₀ : 0.026 ± 0.008 μM)。该化合物还对 TNIK 对 406 种其他激酶表现出优异的选择性。在体外试验中，化合物21k可以有效抑制 CRC 细胞增殖和迁移，并在 HCT116 异种移植小鼠模型中表现出相当大的抗肿瘤活性。它还显示出良好的药代动力学特性。总体而言， 21k可能是针对 TNIK 药物发现的有前途的先导化合物，值得进一步研究。

更新日期：2022-02-10

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