A molecular mystery that could potentially lead to new cancer treatments is solved thanks to a team at Harvard and the Broad Institute of MIT. The researchers discovered how a strange molecule, known as ML210, works to kill drug-resistant cancer cells by inducing a cellular process called ferroptosis. They believe that knowing how ML210 triggers that process could pave the way to developing drugs for treating cancers that are resistant to existing therapies or to prevent resistance in the first place.
Ferroptosis is a kind of cell death where toxic molecules called lipid peroxides build up in a cell. A protein known as GPX4 prevents this from happening by turning them into safer compounds. Previously, researchers wondered whether switching off GPX4 would be an effective method for killing cancer. Later on, scientists found that ML210 binds to GPX4 and triggers ferroptosis, but they didn’t know how.
Now, the Broad Institute and Harvard team have figured it out. When they looked on closer chemical analysis, they found that once ML210 enters the cell, it goes through a two-step transformation.
First, it turns into a compound dubbed JKE-1674, then it converts into another molecule called JKE-1777, which is the form that can bind to GPX4. Of those forms, the team found that JKE-1674 was the most stable outside of cells, and appeared to be selective only for GPX4, making it promising for use in humans and animals. This method could be the start of a new class of cancer drugs that work by inducing ferroptosis.
The team published their research on March 30, 2020, in the journal Nature Chemical Biology.
