Cortistatins Explained
The cortistatins are a group of steroidal alkaloids first isolated in 2006 from the marine sponge Corticium simplex.[1] The cortistatins were first discovered in a search for naturally occurring compounds that inhibit proliferation of human umbilical vein endothelial cells (HUVECs), with cortistatin A being the most potent compound in the class.[2]
The Shair group at Harvard along with collaborators have shown that cortistatin A is a highly potent and selective inhibitor of CDK8 and CDK19, the kinases that associate with Mediator complex.[3] Out of 386 kinases evaluated, cortistatin A only inhibited CDK8 and CDK19, revealing that it is among the most selective kinase inhibitors. It was also shown that cortistatin A potently inhibits growth of acute myeloid leukemia cells and AML in two in vivo mouse models. Identification of dominant drug-resistant alleles of CDK8 and CDK19 demonstrate that these kinases mediate the activity of cortistatin A in AML cells. Thus, inhibition of CDK8 and CDK19 is a new therapeutic approach to AML. Cortistatin A caused selective and disproportionate up-regulation of super-enhancer-associated genes in AML cells which contributed to its anti-leukemic activity. This work indicated that CDK8 and CDK19 are negative regulators of super-enhancer-associated genes in AML.
Di-dehydrocortistatin A suppresses viral replication in cells infected with HIV via binding to the Tat protein.[4]
Cortistatin A was synthesized first by Baran,[5] thereafter by Shair,[6] Myers, and Nicolaou labs.[7]
Notes and References
- 16522087 . 2006 . Aoki . S . Watanabe . Y . Sanagawa . M . Setiawan . A . Kotoku . N . Kobayashi . M . Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex . 128 . 10 . 3148–9 . 10.1021/ja057404h . Journal of the American Chemical Society.
- 17765550 . 2007 . Aoki . S . Watanabe . Y . Tanabe . D . Arai . M . Suna . H . Miyamoto . K . Tsujibo . H . Tsujikawa . K . Yamamoto . H . Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids . 15 . 21 . 6758–62 . 10.1016/j.bmc.2007.08.017 . Bioorganic & Medicinal Chemistry .
- Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. 273–276. 526. 7572. 10.1038/nature14904. Henry E.. Pelish. Brian B.. Liau. Ioana I.. Nitulescu. Anupong. Tangpeerachaikul. Zachary C.. Poss. Diogo H. Da. Silva. Brittany T.. Caruso. Alexander. Arefolov. Olugbeminiyi. Fadeyi. 26416749. 2015. 4641525. 2015Natur.526..273P.
- Mousseau . G. . Clementz . M. A. . Bakeman . W. N. . Nagarsheth . N. . Cameron . M. . Shi . J. . Baran . P. . Fromentin . R. M. . Chomont . N. . 10.1016/j.chom.2012.05.016 . Valente . S. T. . An Analog of the Natural Steroidal Alkaloid Cortistatin a Potently Suppresses Tat-Dependent HIV Transcription . Cell Host & Microbe . 12 . 1 . 97–108 . 2012 . 22817991 . 3403716 .
- Synthesis of (+)-Cortistatin A. Journal of the American Chemical Society. 7241–7243. 2008. 130. 23. 10.1021/ja8023466. 18479104. 2652360. Ryan A.. Shenvi. Carlos A.. Guerrero. Jun. Shi. Chuang-Chuang. Li. Phil S.. Baran.
- Enantioselective Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor of Endothelial Cell Proliferation. Journal of the American Chemical Society. 2008-12-17. 0002-7863. 16864–16866. 130. 50. 10.1021/ja8071918. Hong Myung. Lee. Cristina. Nieto-Oberhuber. Matthew D.. Shair. 19053422. 207132632 .
- Total Synthesis of (+)-Cortistatin A. 10.1002/anie.200803550. 2008. Nicolaou. K. C.. Sun. Ya-Ping. Peng. Xiao-Shui. Polet. Damien. Chen. David Y.-K.. Angewandte Chemie International Edition. 47. 38. 7310–7313. 18704899.