A team of has identified the binding site where drug compounds could activate a key braking mechanism against the runaway growth of many types of cancer.
The discovery marks a critical step toward developing a potential new class of anti-cancer drugs that enhance the activity of a prevalent family of tumor suppressor proteins, the authors say.
The findings, which appear in the leading life sciences journal Cell, are less a story of what than how.
Scientists have known for a while that certain molecules were capable of increasing the activity of the tumor suppressor protein PP2A, killing cancer cells and shrinking tumors in cell lines and animal models -- but without information about the physical site where the molecules interact with the protein, trying to optimize their properties to turn them into actual drugs would require endless trial and error.
"We used cryo-electron microscopy to obtain three-dimensional images of our tool-molecule, DT-061, bound to PP2A," says study co-senior author. "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 this class of molecules SMAPs -- for small molecule activators of PP2A.
The authors demonstrate how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. The 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly.
Along with cancer, PP2A is also dysregulated in a number of other diseases including cardiovascular and neurodegenerative diseases. And the researchers are optimistic the findings could also open opportunities to develop new medicines against diseases like heart failure and Alzheimer's as well.
The new research attacks cancer from the opposite side of the equation, turning on cancer's "off switch" by stabilizing 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," the author adds.
Stabilizing protein phosphatases to target cancer
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