Moniot Sébastien, Forgione Mariantonietta, Lucidi Alessia, Hailu Gebremedhin S, Nebbioso Angela, Carafa Vincenzo, Baratta Francesca, Altucci Lucia, Giacché Nicola, Passeri Daniela, Pellicciari Roberto, Mai Antonello, Steegborn Clemens, Rotili Dante
Department of Biochemistry and Research Center for Bio-Macromolecules, University of Bayreuth , 95440 Bayreuth, Germany.
Department of Drug Chemistry and Technologies, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
J Med Chem. 2017 Mar 23;60(6):2344-2360. doi: 10.1021/acs.jmedchem.6b01609. Epub 2017 Mar 14.
Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report a series of Sirt2 inhibitors based on the 1,2,4-oxadiazole scaffold. These compounds are potent Sirt2 inhibitors active at single-digit μM level by using the Sirt2 substrate α-tubulin-acetylLys40 peptide and inactive up to 100 μM against Sirt1, -3, and -5 (deacetylase and desuccinylase activities). Their mechanism of inhibition is uncompetitive toward both the peptide substrate and NAD, and the crystal structure of a 1,2,4-oxadiazole analog in complex with Sirt2 and ADP-ribose reveals its orientation in a still unexplored subcavity useful for further inhibitor development. Tested in leukemia cell lines, 35 and 39 induced apoptosis and/or showed antiproliferative effects at 10 or 25 μM after 48 h. Western blot analyses confirmed the involvement of Sirt2 inhibition for their effects in NB4 and in U937 cells. Our results provide novel Sirt2 inhibitors with a compact scaffold and structural insights for further inhibitor improvement.
沉默调节蛋白2（Sirt2）是治疗包括癌症在内的神经、代谢和与年龄相关疾病的一个靶点。在此，我们报道了一系列基于1,2,4-恶二唑骨架的Sirt2抑制剂。这些化合物是强效的Sirt2抑制剂，通过使用Sirt2底物α-微管蛋白-乙酰赖氨酸40肽，在个位数微摩尔水平具有活性，而对Sirt1、-3和-5（脱乙酰酶和去琥珀酰化酶活性）在高达100微摩尔时无活性。它们的抑制机制对肽底物和烟酰胺腺嘌呤二核苷酸（NAD）均为非竞争性，并且一种1,2,4-恶二唑类似物与Sirt2和二磷酸腺苷核糖（ADP-ribose）复合物的晶体结构揭示了其在一个尚未探索的亚腔中的取向，这有助于进一步开发抑制剂。在白血病细胞系中进行测试，35和39在48小时后，在10或25微摩尔浓度下诱导细胞凋亡和/或显示出抗增殖作用。蛋白质免疫印迹分析证实了Sirt2抑制参与了它们对NB4和U937细胞的作用。我们的结果提供了具有紧凑骨架的新型Sirt2抑制剂以及用于进一步改进抑制剂结构的见解。
