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-108640A
    HLI373 dihydrochloride
    		MDM2 Inhibitor ≥98.0%
    HLI373 dihydrochloride is an efficacious Hdm2 inhibitor. HLI373 dihydrochloride inhibits the ubiquitin ligase activity of Hdm2. HLI373 dihydrochloride is effective in inducing apoptosis of several tumor cells that are sensitive to DNA-damaging agents. Antimalarial activity.
    HLI373 dihydrochloride
  • HY-12296A
    (3S,5S,6R)-Navtemadlin
    		Control
    (3S,5S,6R)-Navtemadlin is the isomer of Navtemadlin (HY-12296), and can be used as an experimental control. Navtemadlin (AMG 232) is a potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC50 of 0.6 nM. Navtemadlin binds to MDM2 with a Kd of 0.045 nM.
    (3S,5S,6R)-Navtemadlin
  • HY-12287
    YH239-EE
    		MDM2 Inhibitor 98.28%
    YH239-EE, ethyl ester of the free carboxylic acid compound YH239, is a potent p53-MDM2 antagonizing and apoptosis-inducing agent.
    YH239-EE
  • HY-106263B
    Tyroserleutide hydrochloride
    		Inhibitor 99.98%
    Tyroserleutide hydrochloride is a tripeptide isolated from the degradation products of porcine spleen with antitumor activity. Tyroserleutide hydrochloride can upregulate the expression of the tumor suppressor gene PTEN and inhibit the activity of AKT and PDK1. Tyroserleutide hydrochloride inhibits tumor cell proliferation and MDM2 phosphorylation by inhibiting the PI3K/AKT pathway, and also upregulates P21, P27, P53, and induces mitochondrial damage and cell apoptosis.
    Tyroserleutide hydrochloride
  • HY-156967
    BAY 1892005
    		Modulator 99.44%
    BAY 1892005 is a regulator of p53 protein and acts on p53 condensates without causing mutant p53 reactivation.
    BAY 1892005
  • HY-158968
    MMs02943764
    		Modulator ≥98.0%
    MMs02943764 is a 1,2,4-triazole derivative with anticancer activity. MMs02943764 has significant antiproliferative effects on multiple cancer cell lines. PAC, a structural analog of MMs02943764, has significant cytotoxicity against the leukemia cell line K562 (IC50=35.264 μM), reduces the degradation of p53 by inhibiting Mdm2 and Pirh2, and induces K562 cell cycle arrest.
    MMs02943764
  • HY-P1755F
    p53 (17-26), FITC labeled
    		98.31%
    p53 (17-26), FITC labeled is a biological active peptide.
    p53 (17-26), FITC labeled
  • HY-107566
    Conessine
    		Inhibitor 99.87%
    Conessine is an orally active and BBB-penetrable selective histamine H3 receptor antagonist. The pKi values of Conessine for rat and human H3 receptors are 7.61 and 8.27, respectively. Conessine is an inhibitor of the multidrug efflux pump system in Pseudomonas aeruginosa and can enhance the activity of antibiotics. Conessine has antimalarial activity. Conessine can also be used in the research of muscle atrophy.
    Conessine
  • HY-N2602
    Sanggenol L
    		Inhibitor 98.90%
    Sanggenol L induces caspase-dependent and caspase-independent apoptosis in melanoma skin cancer cells. Sanggenol L induces of apoptosis via suppression of PI3K/Akt/mTOR signaling and cell cycle arrest via activation of p53 in p
    Sanggenol L
  • HY-153202
    SLMP53-2
    		Activator 99.96%
    SLMP53-2 is a mutant p53 reactivator. SLMP53-2 restores wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the Hsp70, leading to the reestablishment of p53 transcriptional activity. SLMP53-2 can induce cell cycle arrest, apoptosis and endoplasmic reticulum (ER) stress. SLMP53-2 exhibits antitumor activity.
    SLMP53-2
  • HY-161254
    ATPase-IN-3
    		Activator 99.89%
    ATPase-IN-3 (compound 6) is a ATPase inhibitor. ATPase-IN-3 has Gastroprotective effect in ethanol-induced gastric ulcers by contribution of anti-apoptotic (BCL-2) and tumor suppressor (P53) proteins.
    ATPase-IN-3
  • HY-P5910
    Azurin p28 peptide
    		99.40%
    Azurin p28 peptide is a tumor-penetrated antitumor peptide. Azurin p28 peptide redues proteasomal degradation of p53 through formation of a p28: p53 complex. Azurin p28 peptide induces apoptosis or cell cycle arrest. Azurin p28 peptide inhibits p53-positive tumor growths. Azurin p28 peptide shows antiangiogenic effect by inhibiting phosphorylation of VEGFR-2, FAK and Akt.
    Azurin p28 peptide
  • HY-148402
    p53 Activator 3
    		Activator 98.35%
    p53 Activator 3 (compound 87A) is a potent p53 activator with a SC150 value of <0.05 mM. p53 Activator 3 can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA. p53 Activator 3 shows anti-tumor activity. p53 Activator 3 is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
    p53 Activator 3
  • HY-169369
    TRAP-1
    		Activator 99.69%
    TRAP-1 (XJZ-06-462) is a selective p53Y220C transcriptional activator. TRAP-1 can engage p53Y220C and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription. TRAP-1 rapidly upregulates p21 and other p53 target genes in pancreatic cell lines with p53Y220C. TRAP-1 exhibits higher antiproliferative activity in BxPC-3 (p53Y220C) cells than in A549 cells (p53WT), with IC50 values of 0.531 μM and 3.94 μM, respectively. TRAP-1 can be used for the study of p53Y220C-bearing cancer.
    TRAP-1
  • HY-130437
    p-nitro-Pifithrin-α
    		p53 Inhibitor
    p-nitro-Pifithrin-α, a cell-permeable analog of pifithrin-α, is a potent p53 inhibitor. p-nitro-Pifithrin-α suppresses p53-mediated TGF-β1 expression in HK-2 cells. p-nitro-Pifithrin-α inhibits the activation of caspase-3 by Zika virus (ZIKV) strains. p-nitro-Pifithrin-α attenuates steatosis and liver injury in mice fed a high-fat diet [4]. non-alcoholic fatty liver disease.
    p-nitro-Pifithrin-α
  • HY-153767
    PK095
    		≥98.0%
    PK095 is a p53 mutant stabilizer. PK095 can be used for research of cancer.
    PK095
  • HY-116794
    SF5
    		Inhibitor 99.83%
    SF5 (2,2-Diphenylethyl isothiocyanate) is a sulforaphane analog. SF5 inhibits apoptosis by the JNK-p53-caspase pathway. SF5 can be used as a new renal protective agent for drug-resistant acute renal disease.
    SF5
  • HY-110315
    Ischemin sodium
    		Inhibitor 99.32%
    Ischemin sodium is a CBP bromodomain inhibitor that inhibits p53 interaction with CBP and transcriptional activity in cells. Ischemin sodium salt inhibits p53-induced p21 activation with an IC50 value of 5 µM. Ischemin sodium salt also prevents apoptosis in ischemic cardiomyocytes. Ischemin sodium salt can be used in the study of cardiovascular diseases (such as myocardial ischemia).
    Ischemin sodium
  • HY-17412S1
    Minocycline-d6 sulfate
    		p53 Activator
    Minocycline-d6 sulfate is deuterated labeled Minocycline (HY-17412A). Minocycline is an orally active, potent and BBB-penetrated semi-synthetic tetracycline antibiotic. Minocycline is a hypoxia-inducible factor (HIF)-1α inhibitor. Minocycline shows anti-cancer, anti-inflammatory, and glutamate antagonist effects. Minocycline reduces glutamate neurotransmission and shows neuroprotective properties and antidepressant effects. Minocycline inhibits bacterial protein synthesis through binding with the 30S subunit of the bacterial ribosome, resulting in a bacteriostatic effect.
    Minocycline-d<sub>6</sub> sulfate
  • HY-N12233
    Condurango glycoside A
    		Activator
    Condurango glycoside A is an activator of p53. Condurango glycoside A initiates ROS generation and up-regulates p53 expression. Condurango glycoside A induces apoptosis and pre-mature senescence associated with DNA damage in HeLa cells.
    Condurango glycoside A
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.