The ''The'' () is a grammatical article in English, denoting persons or things already mentioned, under discussion, implied or otherwise presumed familiar to listeners, readers, or speakers. It is the definite article in English. ''The'' is the m ...

cortistatins are a group of

steroidal alkaloid Steroidal alkaloids have organic ring backbones which feature nitrogen-based functional groups. More specifically, they are distinguished by their tetracyclic cyclopentanophenanthrene backbone that marks their close relationship with sterols. They ...

s first isolated in 2006 from the

marine sponge Sponges, the members of the phylum Porifera (; meaning 'pore bearer'), are a basal animal clade as a sister of the diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate through th ...

'' Corticium simplex''. 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. The Shair group at Harvard along with collaborators have shown that cortistatin A is a highly potent and selective inhibitor of

CDK8 Cell division protein kinase 8 is an enzyme that in humans is encoded by the ''CDK8'' gene. Function The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK8 and cyclin C associate with the mediato ...

and CDK19, the kinases that associate with Mediator complex. Out of 386 kinases evaluated, cortistatin A only inhibited CDK8 and CDK19, revealing that it is among the most selective

kinase inhibitors In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule dona ...

. It was also shown that cortistatin A potently inhibits growth of

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...

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 In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity. Because super-enhance ...

-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 Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome an ...

in cells infected with

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

via binding to the Tat protein. Cortistatin A was synthesized by the Shair, Myers, Baran and Nicolaou labs.

Chemical structures

File:Cortistatin A structure.svg, Cortistatin A File:Cortistatin B.svg, Cortistatin B File:Cortistatin C structure.svg, Cortistatin C File:Cortistatin D.svg, Cortistatin D File:Cortistatin E.svg, Cortistatin E File:Cortistatin F.svg, Cortistatin F File:Cortistatin G.svg, Cortistatin G File:Cortistatin H.svg, Cortistatin H File:Cortistatin J structure.svg, Cortistatin J File:Cortistatin K.svg, Cortistatin K File:Cortistatin L.svg, Cortistatin L

References

{{reflist Steroidal alkaloids