Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.

IF 4.9 Q1 CHEMISTRY, MEDICINAL
ACS Pharmacology and Translational Science Pub Date : 2024-12-28 eCollection Date: 2025-01-10 DOI:10.1021/acsptsci.4c00671
Quan Wang, Xinyue Liu, Han Yuan, Fengcai Zhang, Jiafei Wu, Dongjing Yang, Jiang Qian, Yi-You Huang, Guihong Chai, Hai-Bin Luo, Lei Guo
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引用次数: 0

Abstract

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H2S)-donor hybrid PDE10A inhibitor called COS-2080 with a well-defined mechanism of H2S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, COS-2080 demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called COS-2080-DPI has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of COS-2080 on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, COS-2080 effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.

可吸入羰基硫化物供体杂交选择性磷酸二酯酶10A抑制剂通过抑制肿瘤生长因子-β信号传导和激活cAMP/蛋白激酶A/cAMP反应元件结合蛋白(CREB)/p53轴治疗特发性肺纤维化
特发性肺纤维化(IPF)是一种使人衰弱、无法治愈、危及生命的疾病,缺乏有效的治疗方法。磷酸二酯酶10A (PDE10A)过表达在肺纤维化(PF)中起着至关重要的作用。然而,选择性PDE10A抑制剂对肿瘤生长因子-β (TGF-β)/小母亲抗十肢截瘫(Smad)信号通路的影响尚不清楚。在此,我们开发了一种新的羰基硫化物(COS)/硫化氢(H2S)供体杂化PDE10A抑制剂COS-2080,具有明确的H2S释放作用机制。它对PDE10A具有很强的抑制活性,并具有良好的PDE亚家族选择性。此外,COS-2080通过抑制细胞增殖和减缓成纤维细胞向肌成纤维细胞转化(FMT)显示出显著的抗纤维化作用。一种名为COS-2080-DPI的干粉吸入制剂使用超声喷雾冷冻干燥(USFD)技术开发,在博莱霉素诱导的PF小鼠中显示出显著的抗纤维化效果,其剂量约为吡非尼酮的600倍。COS-2080对TGF-β1诱导的FMT具有显著的抗纤维化作用,其主要原因可能是其抑制Smad2/Smad3磷酸化。此外,COS-2080通过激活cAMP/蛋白激酶A (PKA)/CREB通路并潜在地增加p53蛋白水平,有效地减轻了MRC-5细胞的纤维化。我们的研究结果表明,PDE10A的有效抑制可能通过阻断TGF-β信号传导和激活cAMP/PKA/CREB/p53轴,对PF中的FMT具有保护作用。
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来源期刊
ACS Pharmacology and Translational Science
ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)
CiteScore
10.00
自引率
3.30%
发文量
133
期刊介绍: ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.
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