JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yuanbo Hu,Congke Zhao,Wenhua Tan,Mengqi Li,Yu Wang,Ruizhe Gao,Zhuo Chen,Zhenming Jin,Liqing Hu,Qianbin Li
Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.
研究领域:
药理学
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心血管疾病
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药物发现
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分子生物学
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DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2022
·Vol. 23
·期 1
·1-16
·
IF 7.162
Liu Haitao,Zhang Sha,Liu Yi,Ma Jing,Chen Wei,Yin Tao,Li Tongbin,Liang Bin,Tao Ling
Background Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance and artery pressure. Vascular remodeling is associated with the excessive cell proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). In this paper, the effects of heat shock protein-110 (HSP110) on PH were investigated.Methods The C57BL/6 mice and human PASMCs (HPASMCs) were respectively exposed to hypoxia to establish and simulate PH model in vivo and cell experiment in vitro. To HSP110 knockdown, the hypoxia mice and HPASMCs were infected with adeno-associated virus or adenovirus carring the shRNAs (short hairpin RNAs) for HSP110 (shHSP110). For HSP110 and yes-associated protein (YAP) overexpression, HPASMCs were infected with adenovirus vector carring the cDNA of HSP110 or YAP. The effects of HSP110 on PH development in mice and cell proliferation, migration and autophagy of PASMCs under hypoxia were assessed. Moreover, the regulatory mechanisms among HSP110, YAP and TEA domain transcription factor 4 (TEAD4) were investigated.Results We demonstrated that expression of HSP110 was significantly increased in the pulmonary arteries of mice and HPASMCs under hypoxia. Moreover, knockdown of HSP110 alleviated hypoxia-induced right ventricle systolic pressure, vascular wall thickening, right ventricular hypertrophy, autophagy and proliferation of PASMCs in mice. In addition, knockdown of HSP110 inhibited the increases of proliferation, migration and autophagy of HPASMCs that induced by hypoxia in vitro. Mechanistically, HSP110 knockdown inhibited YAP and transcriptional co-activator with PDZ-binding motif (TAZ) activity and TEAD4 nuclear expression under hypoxia. However, overexpression of HSP110 exhibited the opposite results in HPASMCs. Additionally, overexpression of YAP partially restored the effects of shHSP110 on HPASMCs. The interaction of HSP110 and YAP was verified. Moreover, TEAD4 could promote the transcriptional activity of HSP110 by binding to the HSP110 promoter under hypoxia.Conclusion sOur findings suggest that HSP110 might contribute to the development of PH by regulating the proliferation, migration and autophagy of PASMCs through YAP/TAZ-TEAD4 pathway, which may help to understand deeper the pathogenic mechanism in PH development.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Mengqi Li,Yu Wang,Xinru Liang,Congke Zhao,Wenhua Tan,Ruizhe Gao,Yuanbo Hu,Sufang Xiang,Zhuo Chen,Liqing Hu,Qianbin Li
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.
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DOI
PubMed
高影响因子
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