SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Türkiye.
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale, "A. Avogadro", Largo Donegani 2, Novara, Italy.
Drug Dev Res. 2024 Jun;85(4):e22224. doi: 10.1002/ddr.22224.
The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.
哺乳动物细胞质蛋白 SIRT2 是 III 类组蛋白去乙酰化酶家族成员，具有 NAD 依赖性赖氨酸去乙酰化酶/脱酰酶活性。SIRT2 的失调与多种疾病的发病机制有关，包括神经和代谢紊乱以及癌症；因此，SIRT2 成为一个有潜力的治疗靶点。在此，我们通过对我们的命中化合物 STH2 进行结构优化，鉴定了一系列二芳基乙酰胺（ST61-ST90），从而提高了 SIRT2 的抑制效力和选择性。其中，ST72、ST85 和 ST88 分别对 SIRT2 的抑制作用具有选择性，IC50 值分别为 9.97、5.74 和 8.92μM。最后，整个研究还伴随着对接化合物的结合模式和 SIRT2-配体复合物稳定性的计算预测。我们希望我们的发现将为设计 SIRT2 的选择性抑制剂提供有价值的信息。
