3D imaging reveals inner workings of an "off-switch" for cancer
One of the ways the human body can fight off cancer cells is through enzymes known as protein phosphatases, which act as a brake to slow cancer growth. Molecules can be used to ramp up the activity of these enzymes, and through advanced imaging technique scientists have now identified the binding sites they use to do the job, revealing how novel drugs could be used to activate this “off-switch” and keep the disease in check.
The research was carried out by scientists at the University of Michigan and Case Western Reserve University, who focused their attention on a type of protein phosphatase called PP2A. Earlier research had shown how certain molecules could boost the activity of this tumor suppressor protein, resulting in the death of cancer cells and shrinkage of tumors in cell lines and animal studies.
The team sought to take things further and dig into the detail of how this works, hoping to learn more about the physical interactions between those activity-boosting molecules, which they've dubbed SMAPs (small molecule activators of PP2A), and PP2A. The hope was that this understanding could fast-track the transformation of these kinds of molecules into cancer drugs, a process that would otherwise take huge amounts of trial and error to determine the optimal design.
“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, an associate professor of pharmacology and biochemistry at Case Western Reserve University. “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.”
This notion of activating cancer’s off-switch runs counter to another promising form of therapy, drugs that turn off its “on switch.” That arm of cancer research focuses on drugs that inhibit protein kinases, which are enzymes whose dysfunction is vital to the proliferation of cancer cells. Protein kinase inhibitors are drugs that bind to the enzymes and block their function.
Despite these somewhat opposite approaches, the researchers believe the two techniques could be combined to deliver a knockout blow to the cancer, negating its potential to evolve an ability to overpower one therapy or the other. And because PP2A function also plays a role in heart failure and neurodegenerative diseases like Alzheimer’s, the potential of SMAPs mightn’t end there.
“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,” says study author Wei Huang.
The research was published in the journal Cell.
Source: University of Michigan