肺动脉高压（PAH）是一种进行性、致命性的心血管疾病，其特征是肺血管重塑。我们之前的结果表明，热休克蛋白 (Hsp110) 通过增强 Hsp110-STAT3 相互作用而被显着激活，从而诱导血管重塑。破坏这种关联的抑制剂的开发代表了治疗 PAH 的新策略。本研究致力于基于先导化合物2h的结构寻找针对Hsp110-STAT3相互作用的新抑制剂。在化合物 10b 的鉴定中采用融合设计原理并结合结构优化。体外数据表明，10b 通过阻碍 Hsp110 的伴侣功能和 Hsp110-STAT3 相互作用，在抑制肺血管细胞恶性表型方面表现出更大的效力。在缺氧诱导的 PAH 大鼠中，给予 10b 通过抑制 Hsp110-STAT3 关联，显着减弱血管重塑和右心室肥厚。简而言之，这项工作确定了一种新颖且有前途的先导化合物，用于开发针对 Hsp110-STAT3 相互作用的抗 PAH 药物。版权所有 © 2024。由 Elsevier Inc. 出版。

Pulmonary arterial hypertension (PAH) is a progressive and fatal cardiovascular disorder that is characterized by pulmonary vascular remodeling. Our previous results demonstrated that heat shock protein (Hsp110) was significantly activated to induce vascular remodeling by enhancing the Hsp110-STAT3 interaction. The development of inhibitors that disrupt this association represents a novel strategy for the treatment of PAH. This study is committed to finding new inhibitors targeting the Hsp110-STAT3 interaction based on the structure of the lead compound 2h. A fusion design principle was employed in conjunction with structural optimization in the identification of the compound 10b. In vitro data indicates that 10b exhibited greater potency in the inhibition of pulmonary vascular cells malignant phenotypes via impeding the chaperone function of Hsp110 and the Hsp110-STAT3 interaction. In hypoxia-induced PAH rats, administration of 10b significantly attenuated vascular remodeling and right ventricular hypertrophy by inhibiting the Hsp110-STAT3 association. In short, this work identified a novel and promising lead compound for the development of anti-PAH drugs targeting the Hsp110-STAT3 interaction.Copyright © 2024. Published by Elsevier Inc.