Elucidation of novel TRAP1-Selective inhibitors that regulate mitochondrial processes

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Heat shock protein 90 (Hsp90) isoforms have distinct roles in cancer.
• The mitochondrial isoform, TRAP1, is poorly understood due to a lack of specific inhibitors.
• Targeting TRAP1 offers a novel anti-cancer strategy.

Purpose of the Study:

• To develop novel TRAP1-selective inhibitors.
• To investigate TRAP1's biological function using these inhibitors.
• To elucidate the structural basis of TRAP1 inhibition.

Main Methods:

• Design and synthesis of TRAP1-selective small molecules.
• Co-crystallization of inhibitors with TRAP1.
• Structure-based drug design.
• Assessment of cellular effects, including client protein degradation, metabolic changes, and mitochondrial function.

Main Results:

• Novel TRAP1 inhibitors (compounds 35 and 36) were developed.
• Compound 36 exhibits high TRAP1 selectivity (>250-fold over Grp94) with 40 nM potency.
• Inhibitors selectively degraded TRAP1 clients without affecting cytosolic Hsp90 clients or inducing heat shock response.
• Compounds inhibited oxidative phosphorylation (OXPHOS), shifted metabolism to glycolysis, and disrupted mitochondrial membrane potential.

Conclusions:

• TRAP1-selective inhibitors are effective tools for studying TRAP1 biology.
• Targeting TRAP1 impacts cellular metabolism and mitochondrial integrity.
• These findings support TRAP1 as a promising anti-cancer target.