Scientists think they may have found the “off switch” for cancer cells

Shane McGlaun - Apr 21, 2020, 8:51am CDT
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Scientists think they may have found the “off switch” for cancer cells

Scientists from the University of Michigan Rogel Cancer Center and Case Comprehensive Cancer Center have identified a binding site where drug compounds could activate a key braking mechanism in many types of cancer cells. The discovery is said to be a critical step toward developing a potential new class of anti-cancer drugs to enhance the activity of a prevalent family of tumor suppressor proteins.

The scientists say they have known for a while that certain molecules were capable of increasing the activity of tumor suppressor protein PP2A. In animal models, the protein has been able to kill cancer cells and shrink tumors. Scientists say that without information about the physical site where the molecules interact with the protein, trying to optimize the properties to turn them into actual drugs would require endless trial and error.

The team used cryo-electron microscopy to obtain three-dimensional images of the tool-molecule, DT-061 bound to PP2A. Using that microscopy technique, the team was able to see how different parts of the protein were brought together and stabilized by the compound. That information can be used to start developing compounds that can achieve the desired profile, specificity, and potency to translate to the clinic.

Researchers are calling the class of molecules SMAPs, for small molecule activators of PP2A. Cancer and PP2A are both dysregulated in other diseases, including cardiovascular and neurodegenerative diseases. The breakthrough here for cancer could also help develop new medicines for heart failure and Alzheimer’s disease.

The new treatment turns on cancer’s off-switch by stabilizing protein phosphatases whose malfunction removes key brakes on cancer growth. The team says that the biding pocket they have identified provides a launchpad for optimizing the next generation of SMAPs for use in the clinic for treating cancer and possibly other diseases.


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