Harvard scientists reveal how cortistatin A kills leukaemia cells

Cortistatin A (CA) is a natural steroidal alkaloid isolated from sea sponges[1]. Kyriacos Nicolaou totally synthesized the compound and characterized it as an inhibitor of CDK8 and CDK19[2]. Yesterday, a group of Harvard scientists led by Matthew Shair published a paper in Nature[3], revealing the specific mechanism of CA killing leukaemia cells.

It is well known that super-enhancers (SEs) play an important role in tumor pathogenesis. The BRD4 inhibitor I-BET151 downregulated SE-associated genes, thereby inhibiting cancer cells. However, the new paper suggested that CA upregulated these SE-associated genes, yet also inhibited leukaemia cells. Shair believes that cancer cells are sensitive to the dosage of SE-associated genes.

The authors tested CA in approximately 400 kinases, and found that the compound inhibits only CDK8 (IC50=12 nM) and CDK19 in cells. The crystal structure of CA/CDK8 complex (Protein Data Bank ID: 4CRL) reveals the exquisite binding mode. Most kinase inhibitors do not have this type of 3D structure.

Cortistatin A

The researchers measured the efficacy of CA in an AML model using SET-2 cells. The drug afforded a 71% tumour volume reduction, also with no loss in body weight.

CA was totally synthesized via 32 chemical steps. It should be very difficult to make the compound on a large scale. Scientists are trying to find less complex structures that work just like the natural compound.

[1] J Am Chem Soc. 2006, 128(10), 3148-3149.
[2] Angew Chem Int Ed Engl. 2009, 48(47), 8952-8957.
[3] Nature. 2015, doi: 10.1038/nature14904.