TK-129 is an orally active, potent inhibitor of KDM5B with an IC50 of 44 nM and is low-toxicity. TK-129 exhibits cardioprotective effects by inhibiting KDM5B and blocking the KDM5B-associated Wnt pathway. TK-129 can be used in cardiovascular disease studies to reduce isoprenaline-induced myocardial remodelling and fibrosis in vivo, as well as to reduce ang II-induced activation of cardiac fibroblasts in vitro [1].

KDM5:44 nM

TK-129 significantly inhibits KDM5B activity, thereby substantially reducing the activation, migration, and proliferation of myofibroblasts that Ang II induces in vitro [1]. At a concentration of 10 μM over 48 hours, TK-129 demonstrates low cytotoxicity in NRCFs and NRCMs, maintaining cell survival rates above 90% [1]. Furthermore, when applied to NRCFs at concentrations ranging from 0.1 to 0.5 μM for 48 hours, TK-129 effectively targets and inhibits KDM5B activity. This engagement is evidenced by a dose-dependent increase in the expression of the KDM5B substrate, the H3K4me3 protein, indicating TK-129's precision in modulating specific histone modifications [1].

TK-129 demonstrates good bio-safety and efficacy in various mouse models. At a dosage of 2 g/kg administered orally in a single dose, TK-129 was proven safe in mice, with all subjects surviving and exhibiting normal weight gain over two weeks. The compound, at 50 mg/kg given orally twice daily for 24 days, significantly mitigated isoproterenol-induced myocardial remodeling in C57BL/6 mice. Pharmacokinetic (PK) properties were favorable, evidenced by administration at 2 mg/kg intravenously or 10 mg/kg orally in male SD rats, yielding promising pharmacokinetic parameters such as clearance (CL), volume of distribution at steady-state (Vss), half-life (T1/2), time to reach maximum concentration (Tmax), maximum concentration (Cmax), area under the curve from 0 to 24 hours (AUC0-24), and bioavailability (F%).