Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity

Abstract

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is overexpressed in the mitochondria of various cancer cells, reprograms cellular metabolism to enable cancer cells to adapt to harsh tumor environments. As inactivation of TRAP1 induces massive apoptosis in cancer cells in vitro and in vivo, the development of TRAP1-selective inhibitors has become an attractive approach. A series of purine-8-one and pyrrolo[2,3-d]pyrimidine derivatives was developed based on TRAP1 structure and identified to be highly selective in vitro for TRAP1 over the paralogous enzymes, Hsp90 alpha and Grp94. The TRAP I-selective inhibition strategy via utilization of the Asn171 residue of the ATP-lid was investigated using X-ray crystallography and molecular dynamics simulation studies. Among various synthesized potent TRAP I inhibitors, 5f possessed a 65-fold selectivity over Hsp90 alpha and a 13-fold selectivity over Grp94. Additionally, 6f had a half-maximal inhibitory concentration (IC50) of 63.5 nM for TRAP1, with a 78-fold and 30-fold selectivity over Hsp90 alpha and Grp94, respectively.