2. Academic Validation
  3. Discovery of IHMT-15130 as a Highly Potent Irreversible BMX Inhibitor for the Treatment of Myocardial Hypertrophy and Remodeling

Discovery of IHMT-15130 as a Highly Potent Irreversible BMX Inhibitor for the Treatment of Myocardial Hypertrophy and Remodeling

  • ACS Chem Biol. 2025 Jun 20;20(6):1181-1194. doi: 10.1021/acschembio.4c00875.
Shuang Qi 1 2 3 4,  Jiangyan Cao 1 5,  Ting Wu 1 5,  Chenliang Shi 1 5,  Junjie Wang 1 5,  Beilei Wang 1 2 3,  Ziping Qi 1 2 3,  Hong Wu 1 2 3 4,  Yun Wu 1 2 3,  Aoli Wang 1 2 3,  Jing Liu 1 5 2 3 4,  Wenchao Wang 1 5 2 3 4,  Qingsong Liu 1 5 2 3 4
Affiliations

Affiliations

  • 1 Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 2 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 3 Precision Cancer Medicine Engineering Research Center of Anhui Province, Hefei, Anhui 230088, P. R. China.
  • 4 Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
  • 5 University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
PMID: 40388356 DOI: 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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