Qin Luoheng, Aladinskiy Vladimir, Gennert David, Cheng Xin, Liu Jinxin, Liu Tingting, Ren Feng, Zhavoronkov Alex
Insilico Medicine Shanghai Ltd, Shanghai, China.
Insilico Medicine AI, Masdar City, United Arab Emirates.
Expert Opin Ther Pat. 2025 Oct;35(10):1051-1061. doi: 10.1080/13543776.2025.2548585. Epub 2025 Aug 20.
Traf2- and Nck-interacting kinase (TNIK) is a crucial player in various intracellular signaling pathways, including Wnt/β-catenin, cytoskeleton organization, and immune activation. It phosphorylates several key target genes and is widely expressed in different organ systems, such as neural, gastrointestinal, lung, liver, and kidney tissues. TNIK has been implicated in multiple different disease areas, including oncology, neurological diseases, and fibrosis.
This review provides an update of small molecule TNIK inhibitors in patents published from 2008 to 2024.
Despite over 10 patents disclosing multiple scaffolds since 2008, only one inhibitor, INS018_055, has advanced to clinical trials to treat idiopathic pulmonary fibrosis. For the oncology indications, this is largely due to complexities in the relationship between TNIK and oncogenic pathways. Additionally, key characteristics of the molecules, such as kinase selectivity, physicochemical properties, and pharmacokinetic profiles, have played significant roles in determining whether the molecules are drug-like enough to advance to clinical trials.
肿瘤坏死因子受体相关因子2（TRAF2）和Nck相互作用激酶（TNIK）是多种细胞内信号通路中的关键因子，包括Wnt/β-连环蛋白信号通路、细胞骨架组织和免疫激活。它能使多个关键靶基因磷酸化，并在不同的器官系统中广泛表达，如神经、胃肠道、肺、肝和肾组织。TNIK与多种不同的疾病领域有关，包括肿瘤学、神经疾病和纤维化。
本综述提供了2008年至2024年发表的专利中TNIK小分子抑制剂的最新情况。
尽管自2008年以来有超过10项专利披露了多种支架结构，但只有一种抑制剂INS018_055进入了治疗特发性肺纤维化的临床试验。对于肿瘤学适应症，这主要是由于TNIK与致癌途径之间关系的复杂性。此外，分子的关键特性，如激酶选择性、物理化学性质和药代动力学特征，在决定这些分子是否足够类药以推进到临床试验中发挥了重要作用。
