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