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

Abstract

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.

Lysine demethylase 5B transcriptionally regulates TREM1 in human cardiac fibroblasts

“…For instance, elevated KDM5B levels have been observed in mouse hearts following aortic coarctation and in activated cardiac fibroblasts. The KDM5B inhibitor TK-129 has shown efficacy in inhibiting isoproterenol-triggered myocardial fibrosis in mouse models [32]. These findings indicate a detrimental role for high levels of KDM5B and TREM1 in the development of cardiac disease, and inhibiting their expression may benefit disease control.…”

Design, Synthesis, and Evaluation of the Selective and Orally Active LSD1 Inhibitor with the Potential of Treating Heart Failure

“…Many studies have confirmed that post-translational modifications of histones (PTMs) by histone demethylases (KDMs) played indispensable roles in HF. − Our recent study displayed that inhibition of KDM5B reduces Ang II-induced activation of cardiac fibroblasts in vitro and attenuates isoprenaline-induced myocardial remodeling and fibrosis in vivo . KDM5B was also verified to control pathological cardiac hypertrophy and fibrosis. , …”

“…KDM5B was also verified to control pathological cardiac hypertrophy and fibrosis. 9,10 Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase in 2004, is an important member of the highly studied KDM family. 11 As a member of a flavin adenine dinucleotide (FAD)-dependent amine oxidases superfamily, LSD1 catalyzes the demethylation of mono-and dimethylated histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2) via enzymatic oxidation, thereby modifying the state of chromatin.…”

The human antigen R as an actionable super-hub within the network of cancer cell persistency and plasticity

“…Such discrete remodeling depends on the changes in histone marks, as for example H3K4me3, which are themselves dependent on histone demethylases activity. Therefore, direct inhibition of the involved demethylase [27] or inhibition of the activating upstream signaling pathway, as the IGF-1R signaling, represent potential strategies to eliminate slow-proliferating cells [ 17 , 18 ]. (iii) Transcriptional mechanisms: By using a TEAD inhibitor to inhibit the transcriptional YAP-/TEAD/SLUG complex and further restore BMF expression, a team was able, upon enhanced EGFR/MEK inhibition-induced apoptosis, to deplete dormant cells in a model of EGFR -mutant non-small cell lung cancer [28] .…”