ABOVE: A model of ONC201 (red) binding to ClpP (gray) based on the crystal structureMICHAEL 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, as an important target of ONC201, which seems to account for some if not most of its clinical activity,” says Stanley Lipkowitz, chief of the Women’s Malignancy Branch of the National Cancer Institute’s Center for Cancer Resea...