SMTIN-P01 

SMTIN-P01 is a TRAP1 inhibitor that is selective for cytosolic Hsp90 and accumulates in mitochondria. SMTIN-P01 binds to the ATP-binding site of TRAP1 as an ATP mimic, thereby inhibiting ATPase and foldase activities. SMTIN-P01 induces mitochondrial membrane depolarization and proteolytic degradation in cancer cells. SMTIN-P01 exhibits significant cytotoxicity, but shows extremely low toxicity to primary mouse hepatocytes, and does not interfere with SIRT3-related functions or the levels of cytosolic Hsp90 substrates. SMTIN-P01 has important application value in cancer-related research^[1][2][3][4].

SMTIN-P01 (1-6 μM; 30 min preincubation, 3 h ATP incubation) inhibits the ATPase activity of purified recombinant human TRAP1 in a concentration-dependent manner, with greater activity than gamitrinib^[1].
SMTIN-P01 (10 μM; 30 min at 37 °C) induces mitochondrial membrane depolarization in human cervical cancer HeLa cells, indicating disruption of mitochondrial function^[1].
SMTIN-P01 (2 μM; 24 h at 37 °C) does not induce canonical Hsp90 inhibition responses (Hsp70 upregulation, client protein depletion) in human 22Rv1, HeLa, or H460 cancer cells, indicating a mitochondria-specific mode of action distinct from non-targeted Hsp90 inhibitors^[1].
SMTIN-P01 (5-20 μM; 24 h at 37 °C) potently reduces viability of multiple human cancer cell lines (ACHN, HeLa, SK-OV3, 22Rv1, SK-HEP-1, A172, H460, MDA-MB-231) in a concentration-dependent manner, with greater cytotoxicity than PU-H71 and improved activity over gamitrinib in several cancer cell lines, while showing minimal toxicity to normal human corneal cells^[1].
SMTIN-P01 is a mitochondria-targeted TRAP1 inhibitor that binds the TRAP1 N-terminal domain ATP binding site, induces TRAP1 client protein degradation in cancer cells, and does not elicit Hsp90-related off-target effects or heat shock responses^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

838.53

C₃₆H₃₄BrIN₅O₂PS

1695550-43-6

IC1=C(SC2=NC3=C(N2CCCCCC[P+](C4=CC=CC=C4)(C5=CC=CC=C5)C6=CC=CC=C6)N=CN=C3N)C=C7OCOC7=C1.[Br-]

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• [1]. Lee C, et al. Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1. J Am Chem Soc. 2015;137(13):4358-4367.  [Content Brief]

  [2]. Serapian SA, et al. Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives. Trends Pharmacol Sci. 2021;42(7):566-576.  [Content Brief]

  [3]. Kang S, et al. Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1. J Med Chem. 2022;65(24):16155-16172.  [Content Brief]

  [4]. Hu S, et al. Chemical approaches to development of mitochondrial-targeted Hsp90 inhibitor in anti-cancer therapeutics: Mechanism and structure change of mitochondrial Hsp90[J]. Cancer Research, 2017, 77(13_Supplement): 1492-1492.