HSP (Heat shock proteins) are a group of proteins induced by heat shock, the most prominent members of this group are a class of functionally related proteins involved in the folding and unfolding of other proteins. Hsp90 is a molecular chaperone with crucial functions in the development and progression of malignant cell transformation. Tumor-necrosis-factor-receptor associated protein 1 (TRAP1), a mitochondrial paralog of Hsp90 family proteins. In addition, TRAP1 is often overexpressed in various cancer cells. Moreover, TRAP1 rewires cellular metabolism and suppresses cell death pathways in harsh tumor environments. Thus, TRAP1 is a promising target protein for cancer therapeutic development. The main functions of TRAP1 to date include (1) antagonism of the pro-apoptotic activity of cyclophilin D, subsequent inhibition of mitochondrial permeability transition pore opening, and (2) reduction of ROS production to protect cells from oxidative stress, thereby regulating mitochondrial bioenergetics.
SMTIN-T140 (compound 6a) is a potent and selective tumor-necrosis-factor-receptor associated protein 1 (TRAP1) inhibitor. This compound does not inhibit Hsp90 protein. In addition, SMTIN-T140 shows strong anticancer activity without any significant toxicity to normal hepatocytes. However, SMTIN-T140 has IC50 values of 0.3-3.2 μM for seven different cancer cell lines. SMTIN-T140 destabilizes the TRAP1 client proteins, SDHB and SIRT3, and leads to an increase in the phosphorylated form of AMPK, probably due to mitochondrial dysfunction. Consistently, SMTIN-T140 increases mitochondrial ROS production and reduces mitochondrial membrane potential. Especially, in nude mice xenografted with PC3, SMTIN-T140 potently suppresses tumor growth. Meanwhile, SMTIN-T140 does not show any noticeable in vivo toxicity nor affect mouse body weight.
To sum up, SMTIN-T140 is a potent and selective mitochondrial heat shock protein TRAP1 inhibitor with strong anticancer activity.