肿瘤坏死因子受体相关因子2（TRAF2）和非催化区酪氨酸激酶（NCK）相互作用激酶（TNIK）是生发中心激酶（GCK）家族中的一种丝氨酸/苏氨酸激酶。作为Wnt/β-catenin信号通路的关键激活因子，TNIK在肿瘤、纤维化及代谢性疾病等多种疾病的发生发展过程中发挥重要调控作用。近年来，TNIK小分子抑制剂研发经历了从高通量筛选发现到结构导向理性设计、再到人工智能（AI）辅助药物设计的演进历程，但临床转化仍面临“构象悖论”（闭合构象抑制剂酶学活性强但细胞活性弱）、效力-暴露量-毒性三角矛盾等关键挑战。2023年，AI设计的双咪唑骨架抑制剂Rentosertib凭借构象选择性优化与成药性精准调控进入特发性肺纤维化IIa期临床，为突破上述矛盾提供了范例。系统梳理TNIK抑制剂的结构生物学基础，按化学骨架分类综述构效关系与结合模式剖析临床转化瓶颈，并展望AI辅助设计和新型抑制策略的应用前景。

Tumor necrosis factor receptor-associated factor-2- and NCK-interacting protein kinase (TNIK) is a serine/threonine kinase belonging to the germinal center kinase (GCK) family. As a critical activator of the Wnt/β-catenin signaling pathway, TNIK plays an important regulatory role in the pathogenesis and progression of numerous diseases, including tumors, fibrosis and metabolic disorders. In recent years, the R&D of small-molecule TNIK inhibitors has evolved from serendipitous discovery to structure-guided design, and further to artificial intelligence (AI)-aided drug design. However, its clinical translation still faces key challenges such as the “conformational paradox” (closed-conformation inhibitors exhibit strong enzymatic activity but weak cellular activity) and the efficacy-exposure-toxicity triangle dilemma. In 2023, the AI-designed bis-imidazole scaffold inhibitor Rentosertib entered Phase IIa clinical trials for idiopathic pulmonary fibrosis through conformational selectivity optimization and precise druggability regulation, providing a paradigm for breaking through the above contradictions. This paper systematically reviews the structural biology basis of TNIK inhibitors, discusses their structure-activity relationships and binding modes categorized by chemical scaffolds, analyzes the bottlenecks in clinical translation, and prospects the application of AI-assisted design and novel inhibition strategies.

R979.1