Pifithrin-μ

Pifithrin-μ (PFT-μ) is an inhibitor of p53-mediated apoptosis, preventing p53 binding to Bcl-xL and Bcl-2 at the mitochondria without affecting p53 transactivational activities¹ In vitro, PFT-μ binds both p53 (K_d = 0.82 mM) and Bcl-xL (K_d = 0.80 mM).² PFT-μ reduces p53-mediated apoptosis induced by γ-radiation in mouse thymocytes in vitro and protects mice from doses of radiation that cause lethal hematopoietic syndrome. At 25 μM, PFT-μ reduces apoptosis triggered by nutlin-3, which inhibits MDM2/p53 binding and potentiates p53-mediated growth arrest and apoptosis.³ PFT-μ also interacts selectively with heat shock protein 70 (Hsp70), leading to disruption of the association between Hsp70 and many of its co-chaperones and substrate proteins.⁴

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1. Strom, E., Sathe, S., Komarov, P.G., et al. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat. Chem. Biol. 2(9), 474-479 (2006).

2. Hagn, F., Klein, C., Demmer, O., et al. BclxL changes conformation upon binding to wild-type but not mutant p53 DNA binding domain. The Journal of Biological Chemisty 285(5), 3439-3450 (2010).

3. Vaseva, A.V., Marchenko, N.D., and Moll, U.M. The transcription-independent mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells. Cell Cycle 8(11), 1711-1719 (2009).

4. Leu, J.I., Pimkina, J., Frank, A., et al. A small molecule inhibitor of inducible heat shock protein 70. Mol. Cell 36(1), 15-27 (2009).