Sirtris Pharmaceuticals

Sirtris Pharmaceuticals, Inc. was a biotechnology company based in Cambridge, MA that developed therapies for type 2 diabetes, cancer, and other diseases. Founded in 2004 by Harvard University biologist David Sinclair, venture capitalist Christoph Westphal, and serial entrepreneur Andrew Perlman, the company went public in 2007 and was subsequently purchased by GlaxoSmithKline in 2008 for $720 million. It was operated as a business unit of GSK until 2013, when it was absorbed into GSK, where research and development continues.[1] Sirtris's drug discovery was focused on developing activators of sirtuins, a class of enzyme that may mediate benefits of calorie restriction. The company's current lead candidates are SRT2104 and SRT2379, which are both potent activators of the SIRT1 enzyme. These and related molecules are in clinical development. The company's other drug candidate was SRT-501, a proprietary formulation of the compound resveratrol, possibly an activator of the SIRT1 enzyme.[2] Development of SRT-501 was halted by GlaxoSmithKline in late 2010, due to suspected drug-related adverse effects in study participants. The company later focused on developing more potent synthetic activators of SIRT1 and is investigating SIRT3 as another potential drug target.[3] Studies from rivals Amgen and Pfizer cast doubt on whether SIRT1 was directly activated.[4][5] Subsequent work provided evidence that the original conclusions of Sinclair were correct: SIRT1 is directly activated by resveratrol and the synthetic activators, with the activator binding in the N-terminus of SIRT1.[6] A mutation in this N-terminal SIRT1 domain (SIRT1-E230K) was shown to block activation by resveratrol and by synthetic activators from Sirtris, both in vitro and in vivo, largely settling the scientific debate. In 2014, SRT1720 and SRT2104 were shown to extend the health span and the lifespan of mice on a standard diet.[7][8]

References

  1. ↑ "GSK absorbs controversial 'longevity' company : News blog". Nature Blog.
  2. ↑ "Scientists find path to fountain of youth". October 1, 2009.
  3. ↑ Sirtris Pharmaceuticals, Inc. at the Wayback Machine (archived July 1, 2009)
  4. ↑ Beher, Dirk; Wu, John; Cumine, Suzanne; Kim, Ki Won; Lu, Shu-Chen; Atangan, Larissa; Wang, Minghan (2009). "Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity". Chemical Biology & Drug Design. 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076.
  5. ↑ Pacholec, M.; Bleasdale, J. E.; Chrunyk, B.; Cunningham, D.; Flynn, D.; Garofalo, R. S.; Griffith, D.; Griffor, M.; Loulakis, P.; Pabst, B.; Qiu, X.; Stockman, B.; Thanabal, V.; Varghese, A.; Ward, J.; Withka, J.; Ahn, K. (2010). "SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1". Journal of Biological Chemistry. 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984Freely accessible. PMID 20061378.
  6. ↑ Hubbard, B. P.; Gomes, A. P.; Dai, H.; Li, J.; Case, A. W.; Considine, T.; Riera, T. V.; Lee, J. E.; e, S. Y.; Lamming, D. W.; Pentelute, B. L.; Schuman, E. R.; Stevens, L. A.; Ling, A. J. Y.; Armour, S. M.; Michan, S.; Zhao, H.; Jiang, Y.; Sweitzer, S. M.; Blum, C. A.; Disch, J. S.; Ng, P. Y.; Howitz, K. T.; Rolo, A. P.; Hamuro, Y.; Moss, J.; Perni, R. B.; Ellis, J. L.; Vlasuk, G. P.; Sinclair, D. A. (2013). "Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators". Science. 339 (6124): 1216–9. Bibcode:2013Sci...339.1216H. doi:10.1126/science.1231097. PMID 23471411.
  7. ↑ Mitchell, Sarah J.; Martin-Montalvo, Alejandro; Mercken, Evi M.; Palacios, Hector H.; Ward, Theresa M.; Abulwerdi, Gelareh; Minor, Robin K.; Vlasuk, George P.; Ellis, James L.; Sinclair, David A.; Dawson, John; Allison, David B.; Zhang, Yongqing; Becker, Kevin G.; Bernier, Michel; De Cabo, Rafael (2014). "The SIRT1 Activator SRT1720 Extends Lifespan and Improves Health of Mice Fed a Standard Diet". Cell Reports. 6 (5): 836–43. doi:10.1016/j.celrep.2014.01.031. PMID 24582957.
  8. ↑ Mercken, E. M.; Mitchell, S. J.; Martin-Montalvo, A; Minor, R. K.; Almeida, M; Gomes, A. P.; Scheibye-Knudsen, M; Palacios, H. H.; Licata, J. J.; Zhang, Y; Becker, K. G.; Khraiwesh, H; González-Reyes, J. A.; Villalba, J. M.; Baur, J. A.; Elliott, P; Westphal, C; Vlasuk, G. P.; Ellis, J. L.; Sinclair, D. A.; Bernier, M; De Cabo, R (2014). "SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass". Aging Cell. 13 (5): 787–796. doi:10.1111/acel.12220. PMC 4172519Freely accessible.
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