2025-06-04 中国科学院(CAS)
IHMT-15130’s Effects in Angiotensin II-induced Mouse Models of Cardiac Hypertrophy (Image by QI Shuang)
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- https://english.cas.cn/newsroom/research_news/life/202506/t20250605_1045040.shtml
- https://pubs.acs.org/doi/10.1021/acschembio.4c00875
心筋肥大とリモデリングを治療する高力価の非可逆的BMX阻害剤IHMT-15130の発見 Discovery of IHMT-15130 as a Highly Potent Irreversible BMX Inhibitor for the Treatment of Myocardial Hypertrophy and Remodeling
Shuang Qi,Jiangyan Cao,Ting Wu,Chenliang Shi,Junjie Wang,Beilei Wang,Ziping Qi,Hong Wu,Yun Wu,Aoli Wang,Jing Liu,Wenchao Wang,and Qingsong Liu
ACS Chemical Biology Published May 19, 2025
DOI:https://doi.org/10.1021/acschembio.4c00875
Abstract
Cardiac hypertrophy is usually accompanied by many forms of heart disease, including hypertension, vascular disease, ischemic disease, and heart failure, and thus effectively predicts the increased cardiovascular morbidity and mortality. Bone marrow kinase in chromosome X (BMX) has been reported to be the major signaling transduction protein in cardiac arterial endothelial cells and is thought to be involved in the pathology of cardiac hypertrophy. We report here the discovery of a potent irreversible BMX kinase inhibitor, IHMT-15130, which covalently targets cysteine 496 of BMX and exhibits potent inhibitory activity against BMX kinase (IC50: 1.47 ± 0.07 nM). Compared to recently approved BTK/BMX dual inhibitor Ibrutinib, IHMT-15130 displayed selectivity over CSK kinase (IC50 > 25,000 nM), targeting of which may cause severe atrial fibrillation and bleeding. IHMT-15130 effectively reduced the secretion of inflammatory cytokines, inhibited the inflammatory signaling pathway in vitro and in vivo, and alleviated angiotensin II (Ang II)-induced myocardial hypertrophy in a murine model. This study provides further experimental evidence for the application of BMX kinase inhibitors in the treatment of cardiac hypertrophy.