An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Area of Science:

• Oncology
• Cancer Biology
• Mitochondrial Metabolism

Background:

• Metabolic reprogramming is a key feature of cancer, with glycolysis extensively studied for drug development.
• Targeting mitochondrial oxidative phosphorylation (OXPHOS) in tumors remains underexplored due to limited understanding of its essentiality in specific cancer types.

Purpose of the Study:

• To discover and characterize novel inhibitors of mitochondrial oxidative phosphorylation (OXPHOS) for cancer therapy.
• To evaluate the efficacy of a novel complex I inhibitor, IACS-010759, in preclinical cancer models.

Main Methods:

• Discovery of IACS-010759, a small-molecule inhibitor targeting complex I of the mitochondrial electron transport chain.
• Assessment of IACS-010759's effects on cancer cell proliferation and apoptosis in vitro.
• Evaluation of in vivo anti-tumor efficacy and tolerability in brain cancer and acute myeloid leukemia (AML) models.

Main Results:

• IACS-010759 treatment significantly inhibited proliferation and induced apoptosis in OXPHOS-dependent brain cancer and AML models.
• Tumor growth was potently suppressed in vivo by IACS-010759 at well-tolerated doses.
• The drug's efficacy is likely due to energy depletion and impaired nucleotide biosynthesis from reduced aspartate production.

Conclusions:

• IACS-010759 is a potent inhibitor of OXPHOS-dependent cancers, including brain cancer and AML.
• The drug demonstrates promising anti-tumor activity and tolerability in preclinical studies.
• IACS-010759 is advancing to phase 1 clinical trials for relapsed/refractory AML and solid tumors.