Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 30, Issue 16, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127215
Keywords
SIRT6; Small molecule inhibitor; Type 2 diabetes
Categories
Funding
- National Natural Science Foundation of China [21772130]
- National Science and Technology Major Project [2018ZX09711002-011-019, 2018ZX09201018, 2019ZX09301-135]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
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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 mu M against SIRT6 in the Fluor de Lys (FDL) assay. It displayed K-D values of 9.76 mu M and 10 mu M 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 mu M. 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.
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