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-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-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 99.60%
    (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-112816
    MA242
    		MDM2 Inhibitor
    MA242 is a specific dual inhibitor of MDM2 and NFAT1. MA242 directly binds both MDM2 and NFAT1 with high affinity, induces their protein degradation, and inhibits NFAT1-mediated transcription of MDM2. MA242 induces apoptosis in pancreatic cancer cell lines regardless of p53 status.
    MA242
  • HY-158684
    YX-02-030
    		Degrader 99.86%
    YX-02-030M is a PROTAC MDM2 degrader. YX-02-030M inhibits MDM2-p53 binding and VHL-HIF1α binding with IC50s of 63 nM and 1.35 μM respectively. YX-02-030M binds MDM2 and recruits the VHL E3 ubiquitin ligase to initiate MDM2 degradation, and effectively kills p53 mutant or deleted Triple-negative breast cancers (TNBC) cells. (Blue: VHL ligand; Black: linker; Pink: MDM2 inhibitor).
    YX-02-030
  • HY-128553
    Antineoplaston A10
    		Activator 99.84%
    Antineoplaston A10 is an antineoplaston that inhibits the growth of human hepatoma cells by inducing apoptosis. Antineoplaston A10 can be used in the study of liver cancer and breast cancer.
    Antineoplaston A10
  • HY-W034419
    STIMA-1
    		p53 Activator 98.40%
    STIMA-1 can stimulate mutant p53 DNA binding in vitro and induce expression of p53 target proteins and trigger apoptosis in mutant p53-expressing human tumor cells.
    STIMA-1
  • 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-132595
    Teprasiran
    		p53 Inhibitor
    Teprasiran (QPI-1002) is a small interfering RNA that temporarily inhibits p53-mediated cell death that underlies acute kidney injury (AKI).
    Teprasiran
  • 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-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-70027A
    p53 and MDM2 proteins-interaction-inhibitor dihydrochloride
    		MDM2 Inhibitor 99.56%
    p53 and MDM2 proteins-interaction-inhibitor dihydrochloride is an inhibitor of the interaction between p53 and MDM2 proteins.
    p53 and MDM2 proteins-interaction-inhibitor dihydrochloride
  • 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-U00441
    DPBQ
    		p53 Activator 99.02%
    DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. DPBQ elicits expression and phosphorylation of p53 and this effect is specific to tetraploid cells.
    DPBQ
  • HY-B0860S
    Diuron-d6
    		Activator 99.00%
    Diuron-d6 is the deuterium labeled Diuron (HY-B0860). Diuron is an orally active phenylurea herbicide. Diuron inhibits photosynthesis in plants by blocking the formation of ATP and NADH. Diuron increases the production of ROS. Diuron increases expression of p53 in certain cell lines. Diuron has herbicidal activity against annual and perennial broadleaf weeds and grass weeds. Diuron promotes DMBA/BBN-induced bladder cancer. Diuron can be used in breast cancer research.
    Diuron-d<sub>6</sub>
  • HY-W340313
    p53-MDM2-IN-4
    		Inhibitor 99.79%
    p53-MDM2-IN-4 (Example 4) is an inhibitor of p53-MDM2/X protein interaction, with a Ki value of 3.079 μM. p53-MDM2-IN-4 can be used in anti-tumor research.
    p53-MDM2-IN-4
  • HY-111550
    Bragsin2
    		Inhibitor 99.85%
    Bragsin2 is a potent, selective and noncompetitive nucleotide exchange factor BRAG2 inhibitor, with an IC50 of 3 μM. Bragsin2 binds at the interface between the PH domain of BRAG2 and the lipid bilayer, leads BRAG2 unable to activate lipidated Arf GTPase. Bragsin2 affects breast cancer stem cells.
    Bragsin2
  • HY-145937
    PK9327
    		Modulator 98.07%
    PK9327 is a small-molecule stabilizer targeting cavity-creating p53 cancer mutations.
    PK9327
  • HY-173177
    PSF-IN-2
    		Activator 99.85%
    PSF-IN-2 (Compound (C)-30) is a PSF inhibitor with an IC50 value of 0.005 pM. PSF-IN-2 exhibits anti-cancer activity, and its IC50 value for inhibiting the proliferation of 22Rv1 cells is 0.5 μM. PSF-IN-2 activates the p53 signaling pathway by inhibiting the binding of PSF to RNA, inducing the expression of related genes, promoting apoptosis, and inhibiting the cell cycle. PSF-IN-2 can be used in cancer research.
    PSF-IN-2
  • 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
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.