Bioenergetic and proteomic profiling to screen small molecule inhibitors that target cancer metabolisms

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Cancer cells exhibit altered metabolism for survival, distinct from normal cells.
• Targeting cancer-specific metabolic reprogramming is a promising therapeutic strategy.
• Mitochondrial function is crucial for cancer cell bioenergetics.

Purpose of the Study:

• To develop a screening system for identifying small molecules targeting cancer metabolism.
• To investigate novel compounds that inhibit cancer-specific bioenergetic profiles.
• To elucidate the specific mitochondrial targets of identified compounds.

Main Methods:

• Construction of a screening system based on oxygen consumption rate and extracellular acidification rate.
• Screening of the RIKEN Natural Products Depository (NPDepo) chemical library.
• Development of an in vitro reconstitution assay for the mitochondrial electron transport chain.

Main Results:

• Identified unantimycin A and NPL40330 as inhibitors of mitochondrial respiration.
• Unantimycin A targets mitochondrial complex III.
• NPL40330 targets mitochondrial complex I.

Conclusions:

• Novel small molecules targeting cancer metabolism were discovered.
• Unantimycin A and NPL40330 represent potential leads for developing new cancer therapies.
• The identified compounds provide insights into targeting mitochondrial respiration in cancer.