In laboratory tests, a team of Harvard and Sloan Kettering researchers developed compounds that can target and degrade proteins associated with acute myeloid leukemia (AML). It nearly doubled the life expectancy of cancer-bearing mice.
This multitargeted protein degradation method holds promise for developing and delivering therapeutic molecules to inhibit more types of cancer.
Christina Woo, one of the paper’s senior authors and associate professor of chemical biology, said, “Developing new molecules that degrade new targets for different types of cancer is a massive area of ongoing research in the pharmaceutical industry as well as in academia. By altering the targets that are degraded, we gain the ability to treat new cancers.”
The researchers describe how they created the degrader molecules DEG-35 and DEG-77, which identify and break down proteins that contribute to cancer, in their paper published in Cancer Cell. The authors attempted to degrade two proteins, IKZF2 and CK1, which had previously been difficult to target selectively, let alone simultaneously.
The team was able to successfully dial out one protein and dial in another to craft their effective degraders by testing specific chemical features to alter the degradation scope of the molecules.
Proteins linked to cancer and the molecules that can degrade them have huge therapeutic potential. Multiple myeloma is commonly treated with molecules that degrade targets via cereblon, a protein encoded by the CRBN gene. However, when dealing with aggressive cancers like AML, existing protein degradation strategies have been limited.
The researchers created a new space for targeting cancer-promoting proteins previously thought to be inaccessible by tailoring a class of molecules that act like “molecular glue” to promote the degradation of one of the targets.
Woo’s lab generated a series of compounds. It tested them in tissue culture using their expertise in targeted protein degradation and this class of molecules before sending the best ones to the Kharas Lab. They successfully revealed molecular details about interactions on the protein’s binding surface due to their efforts.
Several members of Woo’s lab worked on the project, with Michael Kharas, a member of molecular pharmacology at Sloan Kettering Institute, and members of his lab. The Kharas Lab tested molecules in cells before injecting them into cancer-infected mice for in vivo studies.
In mice, a single injection of DEG-77 resulted in the degradation of IKZF2 and CK1 in the bone marrow and leukemic cells in the spleen. Leukemia cells in the mice’s blood, bone marrow, and spleen underwent increased apoptosis and myeloid differentiation after 24 hours, reducing their ability to form colonies. DEG-77-treated mice had 66-day survival compared to 35-day survival without total body weight loss.
Woo and Kharas believe that their compounds and protein-degradation strategies will be useful in developing drugs to treat a broader range of cancers.
Kharas from Harvard University said, “In the future, we would like to go from a tool compound, a sort of proof of concept, to an orally available compound that will be tested in people. This is one of the most exciting lab approaches because it has the most potential to be put into patients. We are already looking at how we can use the same targets for other cancers.”
Woo said, “Our group is starting to look at ovarian cancer with additional collaborators.”
The Blavatnik Biomedical Accelerator at Harvard University, the Starr Cancer Consortium Translational Commercialization Fund at the Broad Institute, and the Anna Fuller Fund all provided funding for this research.