2. Signaling Pathways
  3. Apoptosis
  4. MDM-2/p53

MDM-2/p53

MDM-2/p53

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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.

Cat. No. Product Name Effect Purity Chemical Structure
  • HY-124586
    Streptonigrin
    		Activator 99.20%
    Streptonigrin (Bruneomycin) is an orally active antibiotic and pan-PAD inhibitor, inhibiting PAD1, PAD2, PAD3 and PAD4 with IC50 of 48.3 μM, 26.1 μM, 0.43 μM and 2.5 μM, respectively. Streptonigrin inhibits SENP1 (IC50 of 0.518 μM) and reduces HIF1α. Streptonigrin increases p53 and Apoptosis. Streptonigrin shows antiviral activity against Rauscher murine leukemia virus. Streptonigrin has immunosuppressive effects. Streptonigrin has antitumor activity against osteosarcoma.
    Streptonigrin
  • HY-108637
    PhiKan 083
    		p53 Activator 98.93%
    PhiKan 083 is a carbazole derivative, which binds to the surface cavity and stabilizes Y220C (a p53 mutant), with a Kd of 167 μM. PhiKan 083 can be used for cancer research.
    PhiKan 083
  • HY-145785A
    ADH-6 TFA
    		Modulator 99.91%
    ADH-6 TFA is a tripyridylamide compound. ADH-6 abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. ADH-6 TFA targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. ADH-6 TFA has the potential for the research of cancer diseases.
    ADH-6 TFA
  • HY-15335
    Nutlin-3b
    		MDM2 Inhibitor 98.78%
    Nutlin-3b, the inactive form of Nutlin-3 (HY-50696), is a p53/MDM2 inhibitor with an IC50 of 13.6 μM. Nutlin-3b is 150 times less potent in binding to MDM2 than Nutlin-3a (HY-10029). Nutlin-3b is promising for research of cancers.
    Nutlin-3b
  • HY-131611
    6-Azuridine
    		99.83%
    6-Azuridine (6-Azauridine) is an orally active purine nucleoside analogue. 6-Azuridine activates autophagic flux, induces Apoptosis that depends on AMPK and p53. 6-Azuridine exhibit both antitumor and antiviral activities.
    6-Azuridine
  • HY-126437
    Poly-L-lysine hydrobromide (MW 30000-70000)
    		Activator
    Poly-L-lysine hydrobromide (MW 30000-70000) is a water-soluble synthetic polypeptide. Poly-L-lysine hydrobromide (MW 30000-70000) downregulates Bcl-2 and upregulates Bax and p53 proteins. Poly-L-lysine hydrobromide (MW 30000-70000) promotes Apoptosis and reduces VEGF expression. Poly-L-lysine hydrobromide (MW 30000-70000) shows anticancer activity against a variety of tumors. Poly-L-lysine hydrobromide (MW 30000-70000) can also be used as a coating material.
    Poly-L-lysine hydrobromide (MW 30000-70000)
  • HY-120373
    MB710
    		98.76%
    MB710, an aminobenzothiazole derivative, is a stabilizer of oncogenic p53 mutation Y220C. MB710 binds tightly to the Y220C pocket and stabilizes p53-Y220C, with a Kd of 4.1 μM. MB710 shows anticancer activity in p53-Y220C cell lines.
    MB710
  • HY-128842
    PROTAC MDM2 Degrader-3
    		MDM2 Inhibitor
    PROTAC MDM2 Degrader-3 is a MDM2 degrader based on PROTAC technology. PROTAC MDM2 Degrader-3 composes of a potent MDM2 inhibitor, linker, and the MDM2 ligand for E3 ubiquitin ligase.
    PROTAC MDM2 Degrader-3
  • HY-128784
    PK11007
    		p53 Activator 98.73%
    PK11007 is a mild thiol alkylator with anticancer activity. PK11007 stabilizes p53 via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. PK11007 induces mutant p53 cancer cell death by increasing reactive oxygen species (ROS) levels.
    PK11007
  • HY-B0639A
    Amifostine trihydrate
    		p53 Activator 99.95%
    Amifostine trihydrate (WR2721 trihydrate) is a broad-spectrum cytoprotective agent and a radioprotector. Amifostine trihydrate selectively protects normal tissues from damage caused by radiation and chemotherapy. Amifostine trihydrate is potent hypoxia-inducible factor-α1 (HIF-α1) and p53 inducer. Amifostine trihydrate protects cells from damage by scavenging oxygen-derived free radicals. Amifostine trihydrate reduces renal toxicity and has antiangiogenic action.
    Amifostine trihydrate
  • HY-122578
    P53R3
    		p53 Inhibitor 99.93%
    P53R3 is a potent p53 reactivator and restores sequence-specific DNA binding of p53 hot spot mutants, including p53R175H, p53R248W and p53R273H. P53R3 induces p53-dependent antiproliferative effects with much higher specificity than PRIMA-1. P53R3 enhances the recruitment of wild-type p53 and p53M237I to several target gene promoters. P53R3 strongly enhances the mRNA, total protein and cell surface expression of the death receptor death receptor 5 (DR5). P53R3 is used for cancer research.
    P53R3
  • HY-W001538
    S-Propargylcysteine
    		Inducer
    S-Propargylcysteine (SPRC), a structural analog of S-allyl cysteine (SAC), is a slow H2S-releasing compound. S-Propargylcysteine reduces Ca2+ accumulation and inflammatory cytokines, inhibits STAT3, and elevates p53 and Bax. S-Propargylcysteine has anti-inflammatory activity and protects mice against acute pancreatitis. S-Propargylcysteine also has cardioprotective, neuroprotective acitivties.
    S-Propargylcysteine
  • HY-134823
    MD-222
    		MDM2 Inhibitor 99.81%
    MD-222 is the first-in-class highly potent PROTAC degrader of MDM2. MD-222 consists of ligands for Cereblon and MDM2. MD-222 induces rapid degradation of the MDM2 protein and activation of wild-type p53 in cells. MD-222 has anticancer effects.
    MD-222
  • HY-B2054
    Tebufenozide
    		p53 Activator 99.41%
    Tebufenozide is a nonsteroidal ecdysone agonist used to control pest. Tebufenozide has cytotoxic and induces apoptosis in HeLa and insect Tn5B1-4 cells.
    Tebufenozide
  • HY-16999
    RO8994
    		MDM2 Inhibitor 99.62%
    RO8994 (Compound 4) is an orally active, highly potent and selective spiroindolinone p53-MDM2 inhibitor with an IC50 value of 5 nM (HTRF binding assays) and 20 nM (MTT proliferation assays). RO8994 induces up-regulation of p53 expression and Apoptosis in wild-type p53 cancer cells. RO8994 also inhibits tumor growth in the tumor xenograft model.
    RO8994
  • HY-128841
    PROTAC MDM2 Degrader-2
    		MDM2 Inhibitor
    PROTAC MDM2 Degrader-2 is an MDM2 PROTAC degrader. PROTAC MDM2 Degrader-2 can induce the self-ubiquitination and degradation of MDM2, thereby upregulating the level of p53 protein. PROTAC MDM2 Degrader-2 has anti-tumor activity and can be used in the study of cancer. (Blue: MDM2 ligand (HY-128836); Black: linker (HY-128833))
    PROTAC MDM2 Degrader-2
  • HY-130684
    MDM2-IN-1
    		MDM2 Inhibitor 98.02%
    MDM2-IN-1 (Compound 30) is a synthetic MDM2-p53 interaction (MDM2) inhibitor and contains the trans (D-)configuration.
    MDM2-IN-1
  • HY-117280
    GN25
    		Activator 98.81%
    GN25 is a specific p53-Snail binding inhibitor with antitumor effects.
    GN25
  • HY-112128
    USP7-IN-3
    		99.06%
    USP7-IN-3 (Compound 5) is an effective and selective allosteric inhibitor of ubiquitin-specific protease 7 (USP7). USP7-IN-3 can be used for research on acute lymphoblastic leukemia.
    USP7-IN-3
  • HY-16664
    SJ-172550
    		MDM2 Inhibitor 99.95%
    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.
    SJ-172550
Cat. No. Product Name / Synonyms Application Reactivity
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Download MDM-2/p53 Signaling Pathway Map.

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.