Qi Shuang, Cao Jiangyan, Wu Ting, Shi Chenliang, Wang Junjie, Wang Beilei, Qi Ziping, Wu Hong, Wu Yun, Wang Aoli, Liu Jing, Wang Wenchao, Liu Qingsong
Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
ACS Chem Biol. 2025 Jun 20;20(6):1181-1194. doi: 10.1021/acschembio.4c00875. Epub 2025 May 19.
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 (IC: 1.47 ± 0.07 nM). Compared to recently approved BTK/BMX dual inhibitor Ibrutinib, IHMT-15130 displayed selectivity over CSK kinase (IC > 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.
心脏肥大通常伴有多种形式的心脏病，包括高血压、血管疾病、缺血性疾病和心力衰竭，因此可有效预测心血管发病率和死亡率的增加。据报道，X染色体上的骨髓激酶（BMX）是心脏动脉内皮细胞中的主要信号转导蛋白，被认为参与心脏肥大的病理过程。我们在此报告一种强效不可逆的BMX激酶抑制剂IHMT-15130的发现，它共价靶向BMX的半胱氨酸496，并对BMX激酶表现出强效抑制活性（IC：1.47±0.07 nM）。与最近批准的BTK/BMX双重抑制剂依鲁替尼相比，IHMT-15130对CSK激酶具有选择性（IC>25,000 nM），靶向CSK激酶可能会导致严重的心房颤动和出血。IHMT-15130有效减少炎症细胞因子的分泌，在体外和体内抑制炎症信号通路，并在小鼠模型中减轻血管紧张素II（Ang II）诱导的心肌肥大。本研究为BMX激酶抑制剂在治疗心脏肥大中的应用提供了进一步的实验证据。
