Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) which located in mitochondria, is thought to promote tumor cell survival and to reprogram energy metabolism in cancer. Previous studies have demonstrated that the inactivation of TRAP1 selectively induced mitochondrial dysfunction and cell death in cancer cells. Therefore, TRAP1 has been suggested as an emerging target protein for anti-cancer drug development. Isopropyl amine of the Hsp90 inhibitor, PU-H71, was replaced with the mitochondria-targeting moiety, triphenyphosphonium, to produce the mitochondria-accumulating TRAP1 inhibitor, SMTIN-P01. To further optimize SMTIN-P01, we have synthesized several SMTIN-P01 derivatives including TPP-PU-X03 with potent TRAP1 inhibitory activities. TPP-PU-X03 increased TRAP1 ATPase enzyme activity while suppressing chaperone activity, suggesting asymmetric effect on dimeric TRAP1 chaperone functions. Electron microscopic analyses showed TPP-PU-X03 shift TRAP1 conformation from open to close conformation, while other TRAP1 or Hsp90 inhibitors stabilizes open conformation. Importantly, TPP-PU-X03 showed improved mitochondria dysfunction and enhanced cytotoxicity to various cancer cells in vitro and in vivo. Collectively, the structure based optimization of current TRAP1 inhibitors may generate potent anti-cancer drugs with novel mechanisms of action.

Citation Format: Sung Hu, Nam Gu Yoon, Byoung Heon Kang. Chemical approaches to development of mitochondrial-targeted Hsp90 inhibitor in anti-cancer therapeutics: Mechanism and structure change of mitochondrial Hsp90 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1492. doi:10.1158/1538-7445.AM2017-1492