CDK8 is asymmetrically loaded at SEs in MOLM-14 cells.
“Once we learned this molecule named cortistatin A was very potent and selective in terms of inhibiting the growth of AML cells, we tested it in mouse models of AML and found that it was as efficacious as any other molecule we had seen, without having deleterious effects,” Shair said. “This suggests we have identified a promising new therapeutic approach.” It’s one that could be available to test in patients relatively soon.
“We synthesized cortistatin A and we are working to develop novel therapeutics based on it by optimizing its drug-like properties,” Shair said.
MOA: The molecule inhibits a pair of nearly identical kinases, called CDK8 and CDK19, that his work indicates play a key role in the growth of AML cells. The kinases operate as part of a poorly understood, massive structure in the nucleus of cells called the mediator complex, which acts as a bridge between transcription factors and transcriptional machinery. Inhibiting these two specific kinases, Shair and colleagues found, doesn’t shut down all transcription, but instead has gene-specific effects.
“One of the first surprises was that it’s affecting a very small number of genes – we thought it might be in the thousands, but it’s in the low hundreds.” They discovered many were associated with DNA regulatory elements: “super-enhancers.”
“Humans have about 220 different types of cells in their body — they all have the same genome, but they have to form things like skin and bone and liver cells,” Shair explained. “In all cells, there are a relatively small number of DNA regulatory elements, called super-enhancers. These super-enhancers drive high expression of genes, many of which dictate cellular identity. A big part of cancer is a situation where that identity is lost, and the cells become poorly differentiated and are stuck in an almost stem-cell-like state.”
While a few promising potential cancer treatments have attacked the disease by down-regulating such cellular identity genes, Shair and colleagues were surprised to find that their molecule actually turned up the activity of those genes in AML cells.
“We tested approximately 400 kinases, and found that it inhibits only CDK8 and CDK19 in cells, which makes it among the most selective kinase inhibitors identified to date,” Shair said. “Having compounds that precisely hit a specific target, like cortistatin A can help reduce side-effects and increase efficacy. In a way, it shatters a dogma because we thought it wasn’t possible for a molecule to be this selective and bind in a site common to all ~500 human kinases, but this molecule does it, and it does it because of its three-dimensional structure. What’s interesting is that most kinase inhibitor drugs do not have this type of three-dimensional structure. Nature is telling us that one way to achieve this level of specificity, is to make molecules more like cortistatin A.” http://otd.harvard.edu/news-events/attacking-acute-myeloid-leukemia
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