Identification of an Hsp110/HDAC6 Dual-Target Inhibitor for the Effective Treatment of Pulmonary Arterial Hypertension via Synergistic Blockade of Vascular Remodeling.

Recent studies suggested that disrupting the Hsp110-STAT3 interaction is a promising strategy for treating pulmonary arterial hypertension (PAH). However, the restricted reduction in p-STAT3 required to prevent vascular remodeling limits Hsp110-STAT3 PPI inhibitor development. Our preliminary studies revealed that HDAC6 activation in HPAECs contributes to p-STAT3 upregulation. Subsequently, a series of Hsp110/HDAC6 dual-target inhibitors were rationally designed and synthesized. Structure-activity relationship studies identified 15n as a potent dual-target inhibitor, effectively interrupting the Hsp110-STAT3 interaction and suppressing HDAC6 activity. In vitro, 15n exhibited a synergistic effect in suppressing the STAT3 signaling pathway by concurrently targeting Hsp110 and HDAC6, thereby inhibiting the abnormal proliferation and migration of the HPAECs. In vivo, compared with combination therapy, 15n demonstrated enhanced suppressive effects on vascular remodeling through synchronous regulation of dual targets. In summary, the present study provides novel research insights into developing novel PAH drugs based on antivascular remodeling strategies and offers a promising lead compound.