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Project TitleModulators for Human Sirt6 in Obesity and Diabetes Treatment and Assays for Screening Same
Track Code5284
Short Description

This invention relates to a method, assay and inhibitors / activators associated with sirtuin 6 (Sirt6) mechanisms for treatment and prevention for obesity and diabetes.

 

Abstract

The Lin group at Cornell has discovered that Sirt6 has unique and robust novel enzymatic activity, 300-fold more efficient than its deacetylase activity, which preferably and efficiently hydrolyzes long chain fatty acyl groups such as myristoyl lysine and palmitoyl lysine. Based on this discovery, a novel fluorogenic assay has been developed to screen for Sirt6 modulators.

 

Lysine fatty acylation is an abundant and important protein modification. One of the fatty acylated proteins is TNFα, a pro-inflammatory mediator. The researchers have proven that Sirt6 regulates TNFα fatty acylation and its secretion in THP-1 cells, a human monocyte cell line, and in bone-marrow-derived mouse macrophage.

 

Stage of development:

1/ A fluorogenic assay was demonstrated to work in vitro and is ready to be used in a commercial setting in vitro.

2/ Inhibitors that selectively target Sirt6 were also identified, and some of them have shown the ability to control cancer cell proliferation. Amongst the selected inhibitors, the inventors have evaluated Thiomyristoyl (TM) peptides and demonstrated that TM peptides are potent inhibitors for Sirt6, are cell-permeable, and increase TNFα fatty acylation in mammalian cells.

 

This technology represents the first discovery of new epigenetic modifications that can be targeted to treat human diseases.

 

Potential Commercial Applications:

  • A fluorogenic high-throughput assay for screening Sirt6 inhibitors or activators
  • Lead compounds for the development of more potent Sirt6 inhibitors, which could be used as treatments for obesity and diabetes

 

Advantages

  • Reliable assays to screen for inhibitors/activators of Sirt6
  • Designed inhibitors for Sirt6
  • Mechanism-based inhibitors
 
Tagssmall molecules, life science, diabetes, metabolic disease
 
Posted DateJul 20, 2012 2:52 PM

Researcher

Name
Hening Lin

Additional Information

  • PCT Application Number WO2012088268
  • Hong Jiang et al. (2013) Sirt6 regulates TNFα secretion via hydrolysis of long chain fatty acyl lysine. Nature 496(7443): 110–113. doi: 10.1038/nature12038
  • Jing Huet al. (2014). A fluorogenic assay for screening Sirt6 modulators. Org Biomol Chem 11(32): 5213–5216. doi: 10.1039/c3ob41138a
  • He B. et al. (2014). Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors. Org Biomol Chem. 12(38):7498-502. doi: 10.1039/c4ob00860j
  • See technology brief D-5041 / D-5596 / D-5625 / D-6362 for Sirt5 and Sirt2.

Licensing Contact

Phillip Owh
607-254-4508
po62@cornell.edu

Files

File Name Description
Technology Brief D5284 SIRT6 Download