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PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.
Drug Discovery Today ( IF 6.5 ) Pub Date : 2020-06-17 , DOI: 10.1016/j.drudis.2020.06.008
Gary A Piazza 1 , Antonio Ward 1 , Xi Chen 1 , Yulia Maxuitenko 1 , Alex Coley 1 , Nada S Aboelella 2 , Donald J Buchsbaum 3 , Michael R Boyd 4 , Adam B Keeton 1 , Gang Zhou 2
Affiliation  

Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth. In this review, we describe the rationale for using the sulindac scaffold to design-out COX inhibitory activity, while improving potency and selectivity to inhibit PDE5 and PDE10 that activate cGMP/PKG signaling to suppress Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.



中文翻译:

PDE5 和 PDE10 抑制激活 cGMP/PKG 信号传导以阻断 Wnt/β-catenin 转录、癌细胞生长和肿瘤免疫。

尽管许多报告得出结论,非甾体抗炎药 (NSAID) 具有抗癌活性,但由于环加氧酶 (COX) 抑制可能会产生致命毒性,因此不建议长期使用这种常见的药物类别。研究表明,负责 NSAID 舒林酸抗癌活性的机制与 COX 抑制无关,而是涉及脱靶磷酸二酯酶 (PDE)。因此,通过靶向 PDE5 和 PDE10 开发更安全、更有效的癌症适应症药物可能是可行的,PDE5 和 PDE10 在各种肿瘤中过表达并且对癌细胞生长至关重要。在这篇综述中,我们描述了使用舒林酸支架设计出 COX 抑制活性的基本原理,

更新日期:2020-08-19
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