Allosteric site identification, virtual screening and discovery of a sulfonamide Hsp110-STAT3 interaction inhibitor for the treatment of hypoxic pulmonary arterial hypertension
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引用次数: 0
Abstract
Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disorder marked by vascular remodeling, which is linked to the malignant phenotypes of pulmonary vascular cells. The prevailing therapeutic approaches for PAH tend to neglect the potential role of vascular remodeling, leading to the clinical prognosis remains poor. Previously, we first demonstrated that heat shock protein (Hsp110) was significantly activated to boost Hsp110-STAT3 interaction, which resulted in abnormal proliferation and migration of human pulmonary arterial endothelial cells (HPAECs) under hypoxia. In the present study, we initially postulated the allosteric site of Hsp110, performed a virtual screening and biological evaluation studies to discover novel Hsp110-STAT3 interaction inhibitors. Here, we identified compound 29 (AN-329/43448068) as the effective inhibitor of HPAECs proliferation and the Hsp110-STAT3 association with good druggability. In vitro, 29 significantly impeded the chaperone function of Hsp110 and the malignant phenotypes of HPAECs. In vivo, 29 remarkably attenuated pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced PAH rats (i.g). Altogether, our data support the conclusion that it not only provides a novel lead compound but also presents a promising approach for subsequent inhibitor development targeting Hsp110-STAT3 interaction.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.