Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.赖氨酸特异性去甲基化酶5B（Lysine-specific demethylase 5B, KDM5B）已被证实为心血管疾病的潜在药物靶点。本研究首次发现，在主动脉弓缩窄（transverse aortic constriction, TAC）处理后的小鼠心脏，以及血管紧张素II（Ang II）诱导活化的心脏成纤维细胞中，KDM5B的表达水平均显著上调。通过基于结构的药物设计与后续优化，我们获得了强效的吡唑类KDM5B抑制剂TK-129，其半抑制浓度（IC50）为0.044 μM。体外实验显示，TK-129可有效抑制Ang II诱导的心脏成纤维细胞活化；该化合物同时展现出良好的药代动力学特性（PK profile），生物利用度F为42.37%；体内实验中，其可减轻异丙肾上腺素（isoprenaline）诱导的心肌重构与纤维化。机制研究表明，心脏成纤维细胞活化过程中KDM5B的上调与Wnt相关通路（Wnt-related pathway）的激活密切相关；而TK-129的心脏保护作用与其抑制KDM5B活性、阻断KDM5B介导的Wnt通路激活有关。综上，TK-129有望成为靶向KDM5、用于治疗心肌重构与纤维化的新型先导化合物。