One step closer to targeted cancer suppression

Scientists from Michigan have found the molecular binding site that will enable targeted drug development towards stabilising a key braking mechanism in multiple types of cancer. Rather than seeking to attack the protein kinases that switch on and speed up cancerous growth, this research looks at molecular compounds that effectively switch growth off by repairing the molecular brakes.

Scientists already knew that protein PP2A could kill cancer cells and shrink tumours in cell lines and animal models and that certain molecules could increase this tumour suppressing activity. Despite this, it would take huge amounts of trial and error to optimise drug properties without this new information on the location where this molecular interaction can take place.

"We used cryo-electron microscopy to obtain three-dimensional images of our tool-molecule, DT-061, bound to PP2A," says study co-senior author Derek Taylor, Ph.D., an associate professor of pharmacology and biochemistry at Case Western Reserve University and member of the Case Comprehensive Cancer Centre.

"This allowed us to see for the first time precisely how different parts of the protein were brought together and stabilized by the compound. We can now use that information to start developing compounds that could achieve the desired profile, specificity and potency to potentially translate to the clinic."

The researchers propose calling these small molecule activators of the PP2A protein SMAPs.

Along with cancer, PP2A is also dysregulated in a several other diseases including cardiovascular and neurodegenerative diseases. The researchers are optimistic the findings could also open opportunities to develop new medicines against diseases like heart failure and Alzheimer's as well.

There has been a lot of activity and excitement in recent years around the development of kinase inhibitors; small molecule compounds that go after the protein kinases whose dysfunction is involved in the explosive growth and proliferation of cancer cells. That is, turning off cancer's "on switch," Leonard explains.

The new research attacks cancer from the opposite side of the equation, turning on cancer's "off switch" by stabilising protein phosphatases whose malfunction removes a key brake on cancer growth.

In the paper, the researchers speculate how a combination of both approaches simultaneously might offer an even more powerful one-two punch -- potentially helping to overcome cancer's ability to evolve to thwart a singular approach.

"The binding pocket we identified provides a launch pad for optimizing the next generation of SMAPs toward use in the clinic -- in cancer, and potentially other diseases," Huang adds.

The team’s research was funded by grants from the National Institutes of Health and an American Heart Association Postdoctoral Fellowship and published in Cell, a leading life sciences journal, under the title 'Selective PP2A Enhancement Through Biased Heterotrimer Stabilization'.