64984-31-2

In addition to its transactivational functions, p53 mediates apoptosis by binding with the anti-apoptotic proteins Bcl-xL and Bcl-2 at the mitochondrial surface. 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 activities In vitro, PFT-μ binds both p53 (K_d = 0.82 mM) and Bcl-xL (K_d = 0.80 mM). 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. 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.

A small molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation

Inhibits p53 binding to mitochondria by reducing its affinity to antiapoptotic proteins Bcl-xL and Bcl-2 but has no effect on p53-dependent transactivation. Pifithrin-μ has also been shown to inhibit HSP70 leading to tumor cell death associated with protein aggregation, impaired autophagy and inhibition of lysosomal function.

ChEBI: 2-phenylethynesulfonamide is a member of benzenes.

A cell-permeable sulfonamide that blocks p53 interaction with Bcl-xL and Bcl-2 proteins and selectively inhibits p53 translocation to mitochondria without affecting the transactivation function of p53. Effectively protects against γ radiation-induced cell death in vitro and animal lethality in vivo. Because Pifithrin-μ targets only the mitochondrial branch of the p53 pathway without affecting the important transcriptional functions of p53, it is superior to Pifithrin-α (Cat. No. 506132) in in vivo studies. Shown to selectively interact with inducible HSP70 and disrupt its functions.

Inhibits p53 binding to mitochondria by reducing its affinity for antiapoptotic proteins Bcl-2 and Bcl-XL. Displays no effect on the transactivational or cell cycle checkpoint control function of p53. Potentially increases reprogramming efficiency of human somatic cells to induced pluripotent stem cells (iPSCs) by silencing p53. Reduces cell death induced by γ -radiation in vitro and protects mice from doses of radiation that cause lethal hematopoietic syndrome. Selectively inhibits heat shock protein 70 (HSP70) activity.

Pifithrin-μ is an inhibitor of p53 binding and anti-apoptotic, which directly inhibits p53 binding to mitochondria as well as to Bcl-xL and Bcl-2 proteins. PFTμ rescues cells from lethal γ-irradiation-induced cell death. Because pifithrin-μ shuts down only the p53-mitochondrial pathway without affecting the transcriptional functions of p53, it is superior to pifithrin-α.

This cell-permeable sulfonamide-based inhibitor and anti-apoptotic factor (FW = 181.20 g/mol; CAS 64984-31-2; Solubility: >10 mg/mL DMSO, <2 mg/mL HO; pK = 8; Symbol = PFTμ and PAS), also known as 2- 2a phenylethynesulfonamide, targets p53 and Heat Shock Protein-70, or HSP 70. Because it only targets the mitochondrial branch of the p53 pathway without affecting the important transcriptional functions of p53, Pifithrin-μ is recommended over Pifithrin-α for in vivo studies. PFTμ exhibits high specificity for p53 and does not protect cells from apoptosis induced by overexpression of the proapoptotic protein Bax or by treatment with dexamethasone. With B-chronic lymphocytic leukemia (CLL) cells, Pifithrin-μ (5–20 μM) initiated apoptosis within 24 hours, with maximal death at 48 hours, as assessed by cell morphology, cleavage of poly (ADP- ribose) polymerase (PARP), caspase-3 activation, and annexin V staining .

This synthetic Hsp70 protein substrate-binding inhibitor (FW = 181.21 g/mol; CAS 64984-31-2; Abbreviation: PES) selectively interacts with the multifunctional, stress-inducible molecular chaperone HSP70, disrupting its association with several of co-chaperones and client proteins. Treatment of cultured tumor cells with PES promotes cell death as a consequence of protein aggregation, impaired autophagy, and inhibition of lysosomal function. (Typical does are 1–10 μg/g injected intraperitoneally in mice, and 1–10 μM in vitro.) PES also exerts profound effects both in vivo and in vitro by: (a) preventing LPS-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, reducing infiltration of inflammatory cells, and promoting liver cell apoptosis; (b) reducing inducible nitric oxide synthase (iNOS) protein expression as well as that of serum nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) content in LPS-stimulated mice; (c) decreasing the mRNA levels of iNOS, TNF-α, and IL-6 in LPS-stimulated liver; (d) attenuating the degradation of inhibitor of κB-α (IκB-α) as well as the phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB) in LPS-stimulated liver . PES also r2+emarkably reduces typically observed increases in intracellular [Ca] and intracellular pH value in LPS-stimulated RAW 264.7 cells. Moreover, PES significantly reduces the increase in Na+/H+ exchanger 1 (NHE1) association to Hsp70 in LPS-stimulated macrophages and liver, suggesting that NHE1-Hsp70 interaction is required for the involvement of NHE1 in the inflammation response. By disrupting HSP70 actions of in multiple cell signaling pathways, PES offers a way to probe the diverse functions of this molecular.

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1) Leu et al. (2009), The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53; Mol. Cell, 36 15 2) Strom et al. (2006), Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation.; Nat. Chem. Biol., 2 474