2. Academic Validation
  3. Design, synthesis and biological evaluation of 2,4,6- trisubstituted triazine derivatives as new nonpeptide small-molecule SIRT5 inhibitors

Design, synthesis and biological evaluation of 2,4,6- trisubstituted triazine derivatives as new nonpeptide small-molecule SIRT5 inhibitors

  • Bioorg Med Chem. 2023 Oct 1:93:117455. doi: 10.1016/j.bmc.2023.117455.
Lijiao Wang 1,  Lei Hu 1,  Jianlin Deng 1,  Suyan Hou 2,  Luohe Mou 1,  Pengcheng Lei 1,  Xi Chen 1,  Jiayu Liu 1,  Yingying Jiang 1,  Rui Xiong 1,  Xiangqin Tian 3,  Weifeng Zhang 1,  Rong Li 1,  Wenyu Yang 1,  Lingling Yang 4
Affiliations

Affiliations

  • 1 College of Food and Bioengineering, Xihua University, Sichuan 610039, China.
  • 2 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 3 Fuan Group Chongqing Kingsday Pharmaceutical Co., LTD, Chongqing 401120, China.
  • 4 College of Food and Bioengineering, Xihua University, Sichuan 610039, China. Electronic address: yangll080808@sina.com.
PMID: 37643500 DOI: 10.1016/j.bmc.2023.117455
Abstract

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 (IC50 = 5.38 µM), and 14 (IC50 = 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.

Keywords

SIRT5 inhibitor; Scaffold-hopping; Sirtuins; Structure−activity relationship; Triazine derivatives.

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