Li Yating, Wang Fuyu, Wang Kexin, Chen Guo, Bai Lan, Shi Jianyou, Yu Dongke
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Department of Geriatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
Bioorg Chem. 2025 Aug;163:108768. doi: 10.1016/j.bioorg.2025.108768. Epub 2025 Jul 19.
Tumor necrosis factor receptor-associated factor-2 and Nck-interacting protein kinase (TNIK), which is a member of the germinal center kinase (GCK) family, represents a potentially crucial target for tumors, fibrosis, inflammation, and neurological diseases. This is due to its role in regulating significant signaling pathways, including Wnt/β-catenin, TGF-β, Merlin and FAK signaling, as well as the PI3K, AKT, and mTOR pathways. To date, numerous TNIK inhibitors with diverse structures and high in vitro enzyme inhibitory activities have been reported. However, their subsequent development has been hindered by issues such as low selectivity, high toxicity, and suboptimal in vivo therapeutic efficacy. This paper aims to comprehensively review the latest progress in the structural characteristics and pharmacological effects of small-molecule TNIK inhibitors. By doing so, it seeks to offer valuable insights and guidance for the future development of more effective TNIK inhibitors.
肿瘤坏死因子受体相关因子2和Nck相互作用蛋白激酶（TNIK）是生发中心激酶（GCK）家族的成员，是肿瘤、纤维化、炎症和神经疾病的潜在关键靶点。这是因为它在调节重要信号通路中发挥作用，包括Wnt/β-连环蛋白、TGF-β、Merlin和FAK信号通路，以及PI3K、AKT和mTOR通路。迄今为止，已报道了许多结构多样且具有高体外酶抑制活性的TNIK抑制剂。然而，它们随后的开发受到低选择性、高毒性和体内治疗效果欠佳等问题的阻碍。本文旨在全面综述小分子TNIK抑制剂的结构特征和药理作用的最新进展。通过这样做，它旨在为更有效的TNIK抑制剂的未来开发提供有价值的见解和指导。
