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

1. 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.
2. 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 .
3. 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.
4. 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 .
5. 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.
6. 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 .
7. 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.