Discovery of Thieno[3,2-4-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3
Discovery of Thieno[3,2-4-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3
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DOI：
10.1021/jm400204k
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发表时间：
2013-05-09
影响因子：
7.3
通讯作者：
Perni, Robert B.
中科院分区：
文献类型：
--
作者：
Disch, Jeremy S.;Evindar, Ghotas;Perni, Robert B.
Sirtuins SIRT1、SIRT2 和 SIRT3 是 NAD(+) 依赖性脱乙酰酶，被认为是代谢、炎症、肿瘤和神经退行性疾病的潜在靶标。使用编码文库技术 (ELT) 亲和筛选 120 万个富含杂环化合物的 DNA 编码小分子文库，该文库鉴定出具有纳摩尔效力的 SIRT1/2/3 泛抑制剂（例如，11c：SIRT1、SIRT2 和 SIRT3 的 IC50 分别 = 3.6、2.7 和 4.0 nM）。随后的旨在改善理化性质的 SAR 研究确定了类似物 28 和 31 等有效药物。对 SIRT3 活性位点中结合的 11c、28 和 31 进行的晶体学研究表明，常见的甲酰胺结合在烟酰胺 C 袋中，并且抑制剂的脂肪族部分延伸穿过底物通道，解释了可观察到的 SAR 这些泛 SIRT1/2/3 抑制剂，代表了一种新型的 化学型，比目前可用的抑制剂更有效，这使得它们成为沉默调节蛋白研究的宝贵工具。
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocyde enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.