新たな心肥大治療薬候補が前臨床モデルで有望な効果を示す(New Drug Candidate Shows Promise Against Cardiac Hypertrophy in Preclinical Models)

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2025-06-04 中国科学院(CAS)

新たな心肥大治療薬候補が前臨床モデルで有望な効果を示す(New Drug Candidate Shows Promise Against Cardiac Hypertrophy in Preclinical Models)IHMT-15130’s Effects in Angiotensin II-induced Mouse Models of Cardiac Hypertrophy (Image by QI Shuang)

中国科学院・合肥物質科学研究院の劉慶松教授らが開発した新薬候補「IHMT-15130」が、心肥大の前臨床モデルで高い効果を示しました。この薬剤は、炎症経路に関与するX染色体上のBMXキナーゼを選択的かつ不可逆的に阻害し、炎症抑制と心筋肥厚の改善という二重の効果を発揮します。マウス実験では心室肥大の顕著な軽減と毒性の欠如が確認され、心血管疾患治療薬としての可能性が注目されています。

<関連情報>

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.

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