Discovery of 5-(4-methylpiperazin-1-yl)-2-nitroaniline derivatives as a new class of SIRT6 inhibitors

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127215. doi: 10.1016/j.bmcl.2020.127215. Epub 2020 Apr 25.

Abstract

SIRT6 is a deacetylase of histone H3 and inhibitors of SIRT6 have been thought as potential agents for treatment of diabetes. Herein we report the discovery of a series of new SIRT6 inhibitors containing the skeleton 1-phenylpiperazine. Among them, compound 5-(4-methylpiperazin-1-yl)-2-nitroaniline (6d) is the most potent one, which showed an IC50 value of 4.93 μM against SIRT6 in the Fluor de Lys (FDL) assay. It displayed KD values of 9.76 μM and 10 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In selectivity assay, 6d showed no activity against other members of the HDAC family (SIRT1-3 and HDAC1-11) at concentrations up to 200 µM. In a mouse model of type 2 diabetes, 6d could significantly increase the level of glucose transporter GLUT-1, thereby reducing blood glucose. Overall, this study provides a promising lead compound for subsequent drug discovery targeting SIRT6.

Keywords: SIRT6; Small molecule inhibitor; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Piperazine / chemical synthesis
  • Piperazine / chemistry
  • Piperazine / pharmacology*
  • Sirtuins / antagonists & inhibitors*
  • Sirtuins / metabolism
  • Structure-Activity Relationship

Substances

  • Aniline Compounds
  • Histone Deacetylase Inhibitors
  • Piperazine
  • 2-nitroaniline
  • SIRT6 protein, human
  • Sirtuins