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Discovery of STAT3 and Histone Deacetylase (HDAC) Dual-Pathway Inhibitors for the Treatment of Solid Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-05-27 , DOI: 10.1021/acs.jmedchem.1c00136 Yuhao Ren 1 , Shanshan Li 1 , Ren Zhu 2 , Chengying Wan 1 , Dongmei Song 1 , Jiawen Zhu 1 , Guiping Cai 1 , Sihui Long 2 , Lingyi Kong 1 , Wenying Yu 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-05-27 , DOI: 10.1021/acs.jmedchem.1c00136 Yuhao Ren 1 , Shanshan Li 1 , Ren Zhu 2 , Chengying Wan 1 , Dongmei Song 1 , Jiawen Zhu 1 , Guiping Cai 1 , Sihui Long 2 , Lingyi Kong 1 , Wenying Yu 1
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Nowadays, simultaneous inhibition of multiple targets through drug combination is an important anticancer strategy owing to the complex mechanism behind tumorigenesis. Recent studies have demonstrated that the inhibition of histone deacetylases (HDACs) will lead to compensated activation of a notorious cancer-related drug target, signal transducer and activator of transcription 3 (STAT3), in breast cancer through a cascade, which probably limits the anti-proliferation effect of HDAC inhibitors in solid tumors. By incorporating the pharmacophore of the HDAC inhibitor SAHA (vorinostat) into the STAT3 inhibitor pterostilbene, a series of potent pterostilbene hydroxamic acid derivatives with dual-target inhibition activity were synthesized. An excellent hydroxamate derivate, compound 14, inhibited STAT3 (KD = 33 nM) and HDAC (IC50 = 23.15 nM) with robust potency in vitro. Compound 14 also showed potent anti-proliferation ability in vivo and in vitro. Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.
中文翻译：
发现用于治疗实体癌的 STAT3 和组蛋白脱乙酰酶 (HDAC) 双通路抑制剂
如今，由于肿瘤发生背后的复杂机制，通过药物组合同时抑制多个靶点是一种重要的抗癌策略。最近的研究表明，组蛋白去乙酰化酶 (HDAC) 的抑制将导致乳腺癌中臭名昭著的癌症相关药物靶标、信号转导和转录激活因子 3 (STAT3) 的补偿激活，这可能会限制抗-HDAC抑制剂在实体瘤中的增殖作用。通过将HDAC抑制剂SAHA（伏立诺他）的药效团并入STAT3抑制剂紫檀芪中，合成了一系列具有双靶点抑制活性的有效紫檀芪异羟肟酸衍生物。一种极好的异羟肟酸酯衍生物，化合物14，抑制 STAT3（K D = 33 nM) 和 HDAC (IC 50 = 23.15 nM)在体外具有强大的效力。化合物14在体内和体外也显示出有效的抗增殖能力。我们的研究为进一步探索提供了第一个 STAT3 和 HDAC 双靶点抑制剂。
更新日期：2021-06-10
中文翻译：
发现用于治疗实体癌的 STAT3 和组蛋白脱乙酰酶 (HDAC) 双通路抑制剂
如今，由于肿瘤发生背后的复杂机制，通过药物组合同时抑制多个靶点是一种重要的抗癌策略。最近的研究表明，组蛋白去乙酰化酶 (HDAC) 的抑制将导致乳腺癌中臭名昭著的癌症相关药物靶标、信号转导和转录激活因子 3 (STAT3) 的补偿激活，这可能会限制抗-HDAC抑制剂在实体瘤中的增殖作用。通过将HDAC抑制剂SAHA（伏立诺他）的药效团并入STAT3抑制剂紫檀芪中，合成了一系列具有双靶点抑制活性的有效紫檀芪异羟肟酸衍生物。一种极好的异羟肟酸酯衍生物，化合物14，抑制 STAT3（K D = 33 nM) 和 HDAC (IC 50 = 23.15 nM)在体外具有强大的效力。化合物14在体内和体外也显示出有效的抗增殖能力。我们的研究为进一步探索提供了第一个 STAT3 和 HDAC 双靶点抑制剂。
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