School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai 201203, China.
State Key Laboratory of Molecular Engineering and Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China.
Molecules. 2020 Sep 30;25(19):4494. doi: 10.3390/molecules25194494.
The discovery of IDO1 and HDAC1 dual inhibitors may provide a novel strategy for cancer treatment by taking advantages of both immunotherapeutic and epigenetic drugs. In this paper, saprorthoquinone () and 13 of its analogues from Hance were investigated for their SAR against IDO1, the results demonstrated the -quinone was a key pharmacophore. Then a series of IDO1 and HDAC dual inhibitors connected by appropriate linkers were designed, synthesized, and evaluated from the hit compound saprorthoquinone (). Among them, compound showed balanced activity against both IDO1 (IC = 0.73 μM) and HDAC1 (IC = 0.46 μM). Importantly, the structure of suggested that an -quinone pharmacophore and a -(2-aminophenyl) amide pharmacophore were necessary for the IDO inhibition and HDAC inhibition respectively. Meanwhile, these two pharmacophore groups should be combined by a pentane linker. Moreover, the binding modes of to the enzyme active site showed that the hydrogen bond with Leu234 of IDO1 appeared to confer increased potency to this class of inhibitors, which may explain the higher activity of . This study provides a new strategy for future IDO1/HDAC dual inhibitors with synergistic antitumor activity started from lead compound .
IDO1 和 HDAC1 双重抑制剂的发现可能为癌症治疗提供新的策略，同时利用免疫治疗和表观遗传药物的优势。在本文中，从 Hance 中分离得到的 saprorthoquinone ()及其 13 种类似物被研究了对 IDO1 的 SAR，结果表明 -醌是一个关键的药效团。然后，从命中化合物 saprorthoquinone ()出发，设计、合成并评估了一系列通过适当连接子连接的 IDO1 和 HDAC 双重抑制剂。其中，化合物 对 IDO1（IC = 0.73 μM）和 HDAC1（IC = 0.46 μM）均表现出平衡的活性。重要的是，化合物 的结构表明 -醌药效团和 -(2-氨基苯基)酰胺药效团分别是 IDO 抑制和 HDAC 抑制所必需的。同时，这两个药效团应该通过戊烷连接子结合。此外， 与酶活性位点的结合模式表明，与 IDO1 的 Leu234 形成氢键似乎赋予了这类抑制剂更高的活性，这可能解释了 更高的活性。本研究为具有协同抗肿瘤活性的新型 IDO1/HDAC 双重抑制剂提供了新的策略，该抑制剂以先导化合物 为起点。
