Development of Novel Inhibitors of Human Mitochondrial Protease ClpP
2021 Harrington Scholar-Innovator
Acute myeloid leukemia (AML), a cancer that starts in the blood-forming cells of the bone marrow, is a disease with generally poor outcomes. The prognosis is especially poor in older patients and those with high-risk cytogenetics, who have a two-year survival rate of less than 15%.
Standard treatment for AML is intensive chemotherapy, possibly augmented by allogenic stem cell transplantation. The combination, however, is frequently not curative and often provides only brief remissions. Therefore, Dr. Schimmer and his colleagues have developed strategies to target vulnerabilities in leukemia cells in the mitochondria, downstream of the genetic mutations.
“Targeting the unique mitochondrial biology in AML may provide new therapeutic options,” Dr. Schimmer says. “Certain AML cells and their progenitor stem cells have the unique metabolic vulnerability of an increased reliance on the mitochondrial protease ClpP. Inhibiting ClpP chemically or genetically kills AML cells that have high ClpP expression, but doesn't kill normal cells.” A high- throughput shRNA screen of 140,000 compounds identified two novel chemical series that inhibited ClpP enzymatic activity and killed ClpP- dependent AML cells. With the assistance of Harrington Discovery Institute, Dr. Schimmer and his team are working to develop and test small molecule agents that selectively inhibit ClpP. These ClpP inhibitors have the potential to target leukemic cells with high-risk mutations and also effectively eradicate the stem cell population that is a primary cause of disease relapse.
Dr. Schimmer notes that, if successful, these agents could potentially be useful not only in leukemia, but other malignancies as well.