College of Food and Bioengineering, Xihua University, Sichuan 610039, China.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Bioorg Med Chem. 2023 Oct 1;93:117455. doi: 10.1016/j.bmc.2023.117455. Epub 2023 Aug 23.
Human sirtuin 5 (SIRT5) participates in a variety of metabolic disorder-associated diseases, including cancer. Inhibition of SIRT5 has been confirmed to provide a new strategy for treatment of related diseases. Previously, we discovered a pyrimidine skeleton inhibitor XIV, which showed low micromolar inhibitory activity against SIRT5. Herein, we utilized the scaffold-hopping strategy to design and synthesize a series of 2,4,6- trisubstituted triazine derivatives. The SAR analysis led to the discovery of several new SIRT5 inhibitors with low micromolar inhibition levels. The most potent compounds 10 (IC = 5.38 µM), and 14 (IC = 4.07 µM) were further confirmed to be the substrate-competitive SIRT5 inhibitors through enzyme kinetic assays, which is consistent with the molecular docking analyses. Fluorescence-based thermal shift assays proved that these compounds may stabilize SIRT5 by binding withprotein.. In addition, compounds 10 and 14 were also revealed to have moderate selectivity to SIRT5 over SIRT1-3. This study will aid further efforts to develop highly potent and selective SIRT5 inhibitors for the treatment of cancer and other related diseases.
人源 sirtuin 5（SIRT5）参与多种代谢紊乱相关疾病，包括癌症。抑制 SIRT5 已被证实为治疗相关疾病的新策略。先前，我们发现了嘧啶骨架抑制剂 XIV，其对 SIRT5 表现出低微摩尔抑制活性。在此，我们利用骨架跃迁策略设计并合成了一系列 2,4,6-三取代三嗪衍生物。SAR 分析导致发现了几种具有低微摩尔抑制水平的新型 SIRT5 抑制剂。最有效的化合物 10（IC = 5.38 µM）和 14（IC = 4.07 µM）通过酶动力学测定进一步确认为 SIRT5 的底物竞争性抑制剂，这与分子对接分析一致。基于荧光的热移位测定证明，这些化合物可能通过与蛋白结合来稳定 SIRT5。此外，化合物 10 和 14 对 SIRT5 的选择性也高于 SIRT1-3。这项研究将有助于进一步开发高效且选择性的 SIRT5 抑制剂，用于治疗癌症和其他相关疾病。
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