The Development of Novel Inhibitors of the Mitochondrial Protease ClpP to Treat Hematological Malignancies

Drug Discovery Award (2021-Present)

Aaron Schimmer, MD, PhD, Princess Margaret Cancer Centre

Aaron Schimmer, MD, PhD

New therapeutics are urgently needed for acute myeloid leukemia (AML), which continues to have poor outcomes in patients. Therefore, novel druggable targets against AML represent an opportunity to improve quality of life and overall survival. Aaron Schimmer and his group have identified the mitochondrial proteasome (ClpP) as a promising new target for the treatment of AML. In normal cell physiology, there is a constant turnover of old and damaged proteins in both the cytoplasm and the mitochondria. In both compartments, large protein complexes called proteasomes degrade these proteins and are a critical means of maintaining cellular health and homeostasis. While there are FDA approved drugs targeting the cytoplasmic proteasome used to treat multiple myeloma, there are no compounds targeting the mitochondrial proteasome ClpP. Schimmer’s group has found that inhibiting ClpP in a subset of AML cell lines with high ClpP expression kills these cells in vitro and in mouse models. Therefore, ClpP levels may be useful as a biomarker for patients who would respond well to ClpP inhibitors.

The Schimmer lab and their collaborators at the Ontario Institute for Cancer Research have discovered a number of potent small-molecule inhibitors which target ClpP. The investigators are expanding and assaying a series of compounds for AML repression. To do so, they are determining the structures of their compounds bound to ClpP and continuing medicinal chemistry efforts to optimize potent, specific, non-toxic, orally available inhibitors. The team is also exploring the role of ClpP in AML proliferation through genetic approaches and by assaying cell viability and mitochondrial function to get a better understanding of which patients would most benefit from ClpP inhibition. These biochemical and biophysical assays, pharmacological studies, and mouse models of AML will advance our understanding of ClpP in AML and accelerate the development of these compounds for use in patients.