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Cortistatins
Chemical compound / From Wikipedia, the free encyclopedia
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]
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Names | |
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IUPAC name
(1R,2R,3S,5R,8β,17β)-3-(Dimethylamino)-17-(isoquinolin-7-yl)-5,8-epoxy-9,19-cyclo-9,10-secoandrosta-9(11),10-diene-1,2-diol | |
Other names
Cortistatine A | |
Identifiers | |
3D model (JSmol) |
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ChEBI | |
ChemSpider | |
PubChem CID |
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UNII | |
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Properties | |
C30H36N2O3 | |
Molar mass | 472.629 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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]