Found: A Cancer Drug’s Mechanism of Action

As ONC201 moves through human clinical trials, scientists finally figure out that the compound and its analogs target a mitochondrial protease.

Written byAshley P. Taylor
| 4 min read
clpp onc201 mechanism of action cancer drug clinical trial

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ABOVE: A model of ONC201 (red) binding to ClpP (gray) based on the crystal structure
MICHAEL ANDREEFF

Scientists have known that the cancer drug ONC201 blocks cells from proliferating and kills tumors in cell and animal models—but they haven’t known exactly how it works, or what its molecular target is. Nevertheless, multiple clinical trials of the drug, in various cancer types, are underway. In 2018, ONC201, made by the Philadelphia-based company Oncoceutics, received a fast track designation from the Food and Drug Administration, meaning it gets expedited review, for the treatment of certain gliomas in adults. Now, two studies published independently this month reveal the drug’s mechanism of action: ONC201 works by activating ClpP, an enzyme that chews up misfolded proteins in mitochondria.

“It’s important to understand how a drug works to understand how best to use it in patients, and in these two studies, they identified ClpP, a mitochondrial protease, ...

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