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

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.