2. Academic Validation
  3. Allosteric site identification, virtual screening and discovery of a sulfonamide Hsp110-STAT3 interaction inhibitor for the treatment of hypoxic pulmonary arterial hypertension

Allosteric site identification, virtual screening and discovery of a sulfonamide Hsp110-STAT3 interaction inhibitor for the treatment of hypoxic pulmonary arterial hypertension

  • Eur J Med Chem. 2024 Dec 5:279:116855. doi: 10.1016/j.ejmech.2024.116855.
Congke Zhao 1,  Yan Wu 1,  Mengqi Li 1,  Wenhua Tan 1,  Yuanbo Hu 1,  Yu Wang 1,  Ruizhe Gao 2,  Liqing Hu 3,  Qianbin Li 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China.
  • 2 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China.
  • 3 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China. Electronic address: huliqing@hunnu.edu.cn.
  • 4 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China. Electronic address: qbli@csu.edu.cn.
PMID: 39260318 DOI: 10.1016/j.ejmech.2024.116855
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.

Keywords

Allosteric site; Heat shock protein 110; Protein-protein interaction; Pulmonary arterial hypertension; Vascular remodeling; Virtual screening.

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