Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Key Laboratory for Green Chemical Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Hubei Engineering Research Center for Advanced Fine Chemicals, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, 206 1st Rd Optics Valley, East Lake New Technology Development District, Wuhan, Hubei 430205, China.
J Med Chem. 2021 Jun 10;64(11):7468-7482. doi: 10.1021/acs.jmedchem.1c00136. Epub 2021 May 27.
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 , inhibited STAT3 ( = 33 nM) and HDAC (IC = 23.15 nM) with robust potency . Compound also showed potent anti-proliferation ability and . Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.
如今，通过药物联合抑制多个靶点是一种重要的抗癌策略，因为肿瘤发生的背后存在复杂的机制。最近的研究表明，组蛋白去乙酰化酶（HDACs）的抑制会通过级联反应导致乳腺癌中臭名昭著的与癌症相关的药物靶点信号转导和转录激活因子 3（STAT3）的代偿性激活，这可能限制了 HDAC 抑制剂在实体瘤中的抗增殖作用。通过将 HDAC 抑制剂 SAHA（伏立诺他）的药效团引入 STAT3 抑制剂紫檀芪中，合成了一系列具有双重靶抑制活性的紫檀芪羟肟酸衍生物。一种优秀的羟肟酸衍生物化合物对 STAT3（=33 nM）和 HDAC（IC=23.15 nM）具有强大的抑制活性。化合物还表现出很强的抗增殖能力和。我们的研究为进一步探索提供了第一个 STAT3 和 HDAC 双重靶点抑制剂。
