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Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1

Changwook Lee, Hye-Kyung Park, Hanbin Jeong

  • 1∥New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 701-310, Korea.

Journal of the American Chemical Society
|March 19, 2015
PubMed

Insights

Researchers developed a novel mitochondrial TRAP1 inhibitor, SMTIN-P01, to target cancer cells more effectively. This new drug shows improved cytotoxicity compared to existing Hsp90 inhibitors by specifically accumulating in mitochondria.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Heat shock protein 90 (Hsp90) and its paralogue TRAP1 are implicated in cancer cell survival and metabolism.
  • Hsp90 inhibitors are explored for cancer therapy, but their mitochondrial targets remain unclear.
  • TRAP1's role in cancer suggests it as a potential therapeutic target.

Purpose of the Study:

  • To identify the specific mitochondrial target of Hsp90 inhibitors in cancer cells.
  • To develop novel inhibitors that effectively target mitochondrial TRAP1.
  • To elucidate the mechanism of TRAP1 ATP hydrolysis and its role in chaperone function.

Main Methods:

  • Determined crystal structures of human TRAP1 complexed with Hsp90 inhibitors.
  • Synthesized a novel mitochondria-targeting TRAP1 inhibitor, SMTIN-P01, by modifying PU-H71.
  • Assessed the cytotoxicity and mode of action of SMTIN-P01 in cancer cells.
  • Determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex.

Main Results:

  • Identified TRAP1 as the primary mitochondrial target, not effectively inhibited by current Hsp90 inhibitors due to poor mitochondrial accumulation.
  • SMTIN-P01 demonstrated enhanced accumulation in mitochondria and significantly improved cytotoxicity compared to PU-H71.
  • Revealed a distinct mode of action for SMTIN-P01.
  • Proposed a molecular mechanism for ATP hydrolysis in TRAP1 based on structural analysis.

Conclusions:

  • TRAP1 is the key mitochondrial target for cancer therapy, requiring specific inhibitors.
  • SMTIN-P01 represents a promising new strategy for targeting mitochondrial TRAP1 in cancer.
  • Understanding TRAP1's ATP hydrolysis mechanism is crucial for developing effective anticancer agents.

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