'Locked' cancer therapeutic activates in tumors, limiting off-target exposure in mice
· Medical Xpressedited by Swati Mestri, reviewed by Robert Egan
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Although there are many cancer treatments available today that effectively eliminate abnormal cells, these therapies may also damage healthy cells, leading to unwanted side effects.
Now, research published in the Journal of Medicinal Chemistry reveals the development of a new therapeutic that is kept "locked" unless it finds itself within a tumor cell.
In mice, the treatment significantly reduced tumor size without accumulating in the liver, suggesting adverse exposures could be reduced and treatment safety improved.
Locking treatment until it reaches tumors
Traditional chemotherapy affects all fast-growing cells in the body. Therefore, scientists are investigating targeted therapies, which aim to focus on specific molecular components within cancer cells. One type of targeted therapy involves modifying cancer cells so that the body's immune system recognizes and eliminates them more efficiently. But sometimes these therapies affect healthy cells, too.
Peng Shi, Mohan Chen and colleagues wanted to employ a different strategy: Keep their treatment compounds "locked" until they reach tumor cells. "By using the intrinsic tumor microenvironment as a molecular switch, this strategy enables more precise and safer targeted protein degradation therapy," Shi explains.
The team developed a cancer therapeutic, abbreviated as Pro-LYTAC, that's activated by glutathione—a peptide found in elevated concentrations in tumors. Once activated, Pro-LYTAC targets a protein exploited by cancer cells to evade immune recognition. Pro-LYTAC directs this protein to the cell's natural cleanup crew, the lysosomes, where the protein gets taken apart. "This degradation removes this protective shield, restoring immune recognition of tumor cells and facilitating a more effective antitumor immune response," Chen explains.
Tumor suppression with less liver buildup
In studies with mouse models of triple-negative breast cancer conducted over two weeks, the researchers found that the Pro-LYTAC therapeutic suppressed tumors better than a control group given saline. Importantly, they also found that Pro-LYTAC was concentrated in the tumors, and only small amounts were present in the animals' livers.
This result suggested that keeping the therapeutic "locked" outside the tumor prevented it from accumulating in the liver and should reduce unwanted side effects, such as liver damage. Though Pro-LYTAC is still in its early stages, the researchers hope it represents a path toward safer and more precise cancer therapy.
Publication details
Mohan Chen et al, Caged Glycan-Antibody Conjugates for Tumor-Selective Activation of Lysosome-Targeting Chimeras, Journal of Medicinal Chemistry (2026). DOI: 10.1021/acs.jmedchem.6c01778
Journal information: Journal of Medicinal Chemistry
Key medical concepts
Triple Negative Breast NeoplasmsLiverGlutathioneLysosomes
Clinical categories
OncologyClinical pharmacology Provided by American Chemical Society Who's behind this story?
Swati Mestri
Swati Mestri holds a bachelor's degree in Electronics Engineering and has worked as a content editor since 2019. She has experience editing research documents across technology, health care, and materials science, and has a particular interest in technology and space. Full profile →
Robert Egan
Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →
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