Discovery of Novel Pyrazole-Based KDM5B Inhibitor <b>TK</b>-<b>129</b> and Its Protective Effects on Myocardial Remodeling and Fibrosis.
Tang K, Jiao LM, Qi YR, Wang TC, Li YL, Xu JL, Wang ZW, Yu B, Liu HM, Zhao W.
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 <b>TK</b>-<b>129</b> (IC<sub>50</sub> = 0.044 μM). <b>TK</b>-<b>129</b> reduced Ang II-induced activation of cardiac fibroblasts <i>in vitro</i>, exhibited good PK profile (<i>F</i> = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis <i>in vivo</i>. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of <b>TK</b>-<b>129</b> were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, <b>TK</b>-<b>129</b> may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.