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

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.
Weining Sun 1,  Xiuli Chen 2,  Shenzhen Huang 2,  Wenpei Li 2,  Chenyu Tian 1,  Shengyong Yang 2,  Linli Li 3
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: ysylilinli@sina.com.cn.
PMID: 32631504 DOI: 10.1016/j.bmcl.2020.127215
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.

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