Grant: Project Grant

Acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes abnormal blood cells. The outcome for most AML patients, especially older ones remains poor. Despite advances in the field that include new drug targets, coupled with an increased understanding of cancer biology, the majority of AML patients eventually relapse and die of the disease. Thus, it is critical to investigate novel ways to target AML using strategies that are rooted in a mechanistic understanding of the disease and the infrastructure AML cells use to survive. The mitochondrion is the "powerhouse of the cell" and is a critical player in several biological pathways that lead to cell death. In particular, AML cells have increased reliance on robust mitochondrial function. As such, proteases that help maintain protein quality control in the mitochondria such as ClpXP are promising therapeutic targets in blood cancers. Using a combined biological, structural, and chemical approach we propose to elucidate the mechanism via which our novel ClpXP inhibitors disrupts its function to fight AML. Our multidisciplinary team comprises a medical doctor specializing in malignant blood disorders, an expert in all aspects of the drug development process, and a pair of structural biologists specializing in structural characterization using spectroscopic and microscopic tools.