Modulators for Sirt2 in Cancer Therapeutics and Assays for Screening Same
- 详细技术说明
- The invention provides methods, assays and compounds associated with sirtuins, specifically Sirt2 mechanisms, for treatment and prevention of cancer.
- *Abstract
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The Lin group at Cornellhas developed assays to screen for Sirt2 or Sirt5 modulators. Inhibitors thatselectively target Sirt2 and Sirt5 have also been identified, and some of themhave been shown to be able to control cancer cell proliferation.
Sirt2 (D-5625)
The researchers havegained evidence supporting human Sirt2 protein as a new target for cancertreatment. The D-5625 invention describes a new group of small moleculeinhibitors for treatment of cancer through targeting Sirt2, the only cytosolicsirtuin. SIRT2 specific knockdown can efficiently and completely inhibit breastcancer cell (MCF7) proliferation, as well as triple-negative breast cancercells (MDA-MB-231 and MDA-MB-468), suggesting that Sirt2 is a potential targetfor treating breast cancer. The researchers’ data show that a Thiomyristoyllysine compound (TM) - an isolated inhibitor with high specificity for Sirt2 -inhibits many cancer cell lines in soft agar assay and effectively shrinks tumorin a mouse xenograft model. TM is then a potent Sirt2-specific inhibitor with abroad anticancer effect in various human cancer cells including brain, lung,breast cancers, and mouse models of breast cancer.
Furthermore,mechanistically Sirt2 inhibition promotes c-Myc ubiquitination and degradationand it has been demonstrated that TM can effectively decrease the levels ofc-Myc in many cancer cell lines by promoting the proteolytic degradation ofc-Myc without affecting its transcription.
PotentialApplications
- Sirt2-specific inhibitor as an anti-cancer drugcandidate
Advantages
- Thiomyristoylcompound (TM) presents highaffinity, high selectivity, and high specificity to Sirt2
- Inhibitionof cancer cell proliferation with minimal effect on normal cells.
See also inventionsrelated to Sirt 5 (D-5041 and D-5596), Sirt6 (D-5284), and novelcompounds inhibiting specifically to Sirt 2 and 5 (D-6362).
- *Licensing
- PhillipOwh607-254-4508po62@cornell.edu
- 其他
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- Patentissued in the U.S. under 9,359,293,U.S. divisional patent application under2016/0279091,and filed in Europe, China, India.
- Jing H.,& al. (2016). A SIRT2-Selective Inhibitor Promotes c-Myc OncoproteinDegradation and Exhibits Broad Anticancer Activity. Cancer Cell 29(3):297-310. DOI: 10.1016/j.ccell.2016.02.007
- “Researchprobes key protein's role in cancer cell growth” Cornell Chronicle, January24, 2018
- “Enzymeinhibitor looks promising against cancer” Cornell Chronicle, March 21, 2016
- 国家/地区
- 美国
