1. Apoptosis
  2. MDM-2/p53

MDM-2/p53

The p53 tumor suppressor is a principal mediator of growth arrest, senescence, and apoptosis in response to a broad array of cellular damage. p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Under stress conditions, the p53 protein accumulates in the cell, binds in its tetrameric form to p53-response elements and induces the transcription of various genes.

MDM-2 is transcriptionally activated by p53 and MDM-2, in turn, inhibits p53 activity in several ways. MDM-2 binds to the p53 transactivation domain and thereby inhibits p53-mediated transactivation. MDM-2 also contains a signal sequence that is similar to the nuclear export signal of various viral proteins and, after binding to p53, it induces its nuclear export. As p53 is a transcription factor, it needs to be in the nucleus to be able to access the DNA; its transport to the cytoplasm by MDM-2 prevents this. Finally, MDM-2 is a ubiquitin ligase, so is able to target p53 for degradation by the proteasome.

In many tumors p53 is inactivated by the overexpression of the negative regulators MDM2 and MDM4 or by the loss of activity of the MDM2 inhibitor ARF. The pathway can be reactivated in these tumors by small molecules that inhibit the interaction of MDM2 and/or MDM4 with p53. Such molecules are now in clinical trials.

View MDM-2/p53 Pathway Map

MDM-2/p53 Related Products (47):

Cat. No. Product Name Effect Purity
  • HY-15484
    Pifithrin-α hydrobromide p53 Inhibitor 98.28%
    Pifithrin-α hydrobromide is a p53 inhibitor which blocks its transcriptional activity and prevents cells from apoptosis.
  • HY-15676
    RG7388 MDM2 Inhibitor 99.97%
    RG7388 is a potent and selective MDM2 antagonist, inhibiting p53-MDM2 binding, with an IC50 of 6 nM.
  • HY-10029
    Nutlin 3a MDM2 Inhibitor 98.11%
    Nutlin 3a is an active enantiomer of Nutlin-3, acts as a murine double minute (MDM2) antagonist that inhibits MDM2-p53 interactions and stabilizes the p53 protein, and thereby induces cell cycle arrest and apoptosis.
  • HY-12296
    AMG 232 MDM2 Inhibitor 99.73%
    AMG 232 is a potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC50 of 0.6 nM. AMG 232 binds to MDM2 with a Kd of 0.045 nM.
  • HY-50696
    Nutlin 3 MDM2 Inhibitor 98.32%
    Nutlin 3 is a commercial available p53-MDM2 inhibitor, with Ki of 90 nM.
  • HY-101266
    Milademetan MDM2 Inhibitor
    Mliademetan is a specific MDM2 inhibitor, a pharmaceutical composition for use in treating acute myeloid leukemia (AML).
  • HY-12734
    AM-8735 MDM2 Inhibitor
    AM-8735 is a potent and selective MDM2 inhibitor with an IC50 of 25 nM.
  • HY-10959
    RG7112 MDM2 Inhibitor 99.94%
    RG7112 is the first clinical and orally available MDM-2/p53 inhibitor designed to occupy the p53-binding pocket of MDM2, with the Kd value of 11 nM.
  • HY-16702A
    Pifithrin-β hydrobromide p53 Inhibitor 99.90%
    Pifithrin-β is a potent p53 inhibitor with an IC50 of 23 μM.
  • HY-15695
    Puromycin aminonucleoside p53 Activator 98.31%
    Puromycin aminonucleoside is the aminonucleoside portion of the antibiotic puromycin, and a puromycin analog which does not inhibit protein synthesis or induce apoptosis.
  • HY-18986
    SAR405838 MDM2 Inhibitor 98.95%
    SAR405838 is a highly potent and selective MDM2 inhibitor, binds to MDM2 with Ki= 0.88 nM and has high specificity over other proteins.
  • HY-19980
    PRIMA-1Met p53 Activator >99.0%
    PRIMA-1MET restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. PRIMA-1MET also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance.
  • HY-18658
    NVP-HDM201 MDM2 Inhibitor 99.19%
    NVP-HDM201 (HDM201) is a potent and highly specific MDM-2/p53 inhibitor currently under phase I clinical trial.
  • HY-15954
    NVP-CGM097 MDM2 Inhibitor 98.32%
    NVP-CGM097 is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.
  • HY-13424
    RITA p53 Activator
    RITA is an inhibitor of p53-HDM-2 interaction, binds to p53dN, with a Kd of 1.5 nM, and also induces DNA-DNA cross-links.
  • HY-P0121
    ReACp53 p53 Activator 99.65%
    ReACp53 could inhibit p53 amyloid formation and rescue p53 function in cancer cell lines. Sequence: H-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Pro-Ile-Leu-Thr-Arg-Ile-Thr-Leu-Glu-OH.
  • HY-19980A
    PRIMA-1 p53 Activator >98.0%
    PRIMA-1 is a mutant p53 reactivator, restores the sensitivity of TP53 mutant-type thyroid cancer cells to the histone methylation inhibitor 3-Deazaneplanocin A.
  • HY-17493
    MI-773 MDM2 Inhibitor >98.0%
    MI-773 is a new small molecule inhibitor of the MDM2-p53 interaction, binds to MDM2 with high affinity (Ki=0.88 nM) and blocks the p53-MDM2 interaction.
  • HY-15510B
    Tenovin 6 Hydrochloride p53 Activator >98.0%
    Tenovin-6 Hydrochloride is a water soluble inhibitor of SIRT1 and SIRT2, slightly inhibits HDAC8, and is also a potent activator of p53, with IC50s of 21 μM, 10 μM, 67 μM for SirT1, SirT2, and SirT3, respectively.
  • HY-16664
    SJ-172550 MDM2 Inhibitor >98.0%
    SJ-172550 is a small molecule inhibitor of MDMX; competes for the wild type p53 peptide binding to MDMX with an EC50 of 5 μM.
mdm-2-p53-map.png

p53 is at the centre of biological interactions that translates stress signals into cell cycle arrest or apoptosis. Upstream signaling to p53 increases its level and activates its function as a transcription factor in response to a wide variety of stresses, whereas downstream components execute the appropriate cellular response. 

 

Cell Stress: p53 induction by acute DNA damage begins when DNA double-strand breaks trigger activation of ATM, a kinase that phosphorylates the CHK2 kinase, or when stalled or collapsed DNA replication forks recruit ATR, which phosphorylates CHK1. p53 is a substrate for both the ATM and ATR kinases, as well as for CHK1 and CHK2, which coordinately phosphorylate p53 to promote its stabilization. These phosphorylation events are important for p53 stabilization, as some of the modifications disrupt the interaction between p53 and its negative regulators MDM2 and MDM4. MDM2 and MDM4 bind to the transcriptional activation domains of p53, thereby inhibiting p53 transactivation function, and MDM2 has additional activity as an E3 ubiquitin ligase that causes proteasome-mediated degradation of p53. Phosphorylation also allows the interaction of p53 with transcriptional cofactors, which is ultimately important for activation of target genes and for responses such as cell cycle arrest, DNA repair, apoptosis and senescence. Non-receptor tyrosine kinase c-Abl can also be activated by DNA damage. Then the JNK/p38 is activated and leads to p53 activation[1][2]

 

Oncogenic signaling: The response to oncogene activation depends on the binding of ARF to MDM2. ARF is normally expressed at low levels in cells. Inappropriately increased E2F or Myc signals, stemming from oncogene activation, leads to the increased expression of ARF, which inhibits MDM2 by blocking its E3 ubiquitin ligase activity, uncoupling the p53-MDM2 interaction, thereby segregating it from nucleoplasmic p53[3].

 

The PI3K-Akt pathway activates MDM2 and increases the ubiquitination of p53. 

 

Reference:
[1]. Chène P, et al. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 2003 Feb;3(2):102-9.
[2]. Brown CJ, et al. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009 Dec;9(12):862-73. 
[3]. Polager S, et al. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009 Oct;9(10):738-48. doi: 10.1038/nrc2718.

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