2. Academic Validation
  3. Design, synthesis and optimization of pyrazolo[3,4-b] pyridine derivatives as Hsp110-STAT3 interaction disruptors for the treatment of pulmonary arterial hypertension

Design, synthesis and optimization of pyrazolo[3,4-b] pyridine derivatives as Hsp110-STAT3 interaction disruptors for the treatment of pulmonary arterial hypertension

  • Bioorg Chem. 2024 Oct 14:153:107888. doi: 10.1016/j.bioorg.2024.107888.
Mengqi Li 1,  Congke Zhao 1,  Honglin Xiang 2,  Yu Wang 1,  Ruizhe Gao 2,  Qinling Cai 2,  Qingsong Chen 1,  Zhuo Chen 1,  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: 39423772 DOI: 10.1016/j.bioorg.2024.107888
Abstract

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.

Keywords

Heat shock protein 110; Protein–protein interaction; Pulmonary arterial hypertension; Structure–activity relationship; Vascular remodeling.

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