TK-129 is an orally active, low-toxicity, potent KDM5B inhibitor (with high affinity; IC50=44 nM). TK-129 exerts cardioprotective effects by inhibiting KDM5B and blocking the KDM5B-associated Wnt pathway. TK-129 reduces ang II-induced activation of cardiac fibroblasts in vitro and reduces isoprenaline-induced myocardial remodelling and fibrosis in vivo. TK-129 can be used in studies of cardiovascular disease.In Vitro:TK-129 mediates inhibition of KDM5B activity significantly reduces the activation, migration, and proliferation of myofibroblasts induced by Ang II in vitro.
TK-129 (10 μM; 48 h) shows low cytotoxicity in NRCFs and NRCMs.
TK-129 (0.1, 0.2, 0.3, 0.4, 0.5 μM; 48 h) can engage toand inhibit KDM5B activity in NRCFs.In Vivo:TK-129 (2 g/kg; p.o.; single) shows good bio-safety in mice.
TK-129 (50 mg/kg; p.o.; twice daily for 24 days) effectively reduces isoproterenol-induced pathological myocardial remodeling in vivo.
TK-129 (2 or 10 mg/kg; i.v. or p.o.; single) demonstrates favorable PK properties in vivo.