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

MDM-2/p53

MDM-2/p53

Related Products

PDF 0.55 MB

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-W011434
    Triglycidyl isocyanurate
    		p53 Activator 99.56%
    Triglycidyl isocyanurate (TGIC; Teroxirone) is a triazene triepoxide with antiangiogenic and antineoplastic activities. Triglycidyl isocyanurate inhibits the growth of non-small-cell-lung cancer cells via?p53 activation. Triglycidyl isocyanurate induces cell apoptosis. Triglycidyl isocyanurate can be used for cancer research.
    Triglycidyl isocyanurate
  • 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
  • HY-123950
    MMRi64
    		Inhibitor 99.42%
    MMRi64 disrupts Mdm2-MdmX interactions. MMRi64 downregulates Mdm2 and MdmX in leukemia cells. MMRi64 induces p53 accumulation, and induces the apoptotic arm of the p53 pathway in leukemia/lymphoma cells. MMRi64 can be used for cancer research.
    MMRi64
  • 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-122753
    SLMP53-1
    		Activator 99.25%
    SLMP53-1 is a wild-type and mutant p53 reactivator with promising antitumor activity. SLMP53-1 mediates the reprograming of glucose metabolism in cancer cells. SLMP53-1 depletes angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels.
    SLMP53-1
  • HY-P3509
    PNC-28
    		98.20%
    PNC-28 is a peptide from the mdm-2-binding domain (residues 17–26) of the p53 protein which contains a membrane crossing-penetratin sequence. PNC-28 can be used for pancreatic cancer research.
    PNC-28
  • HY-117857
    MRT00033659
    		p53 Activator 99.77%
    MRT00033659 is a potent broad-spectrum kinase inhibitor of CK1 (IC50=0.9 μM for CK1δ) and CHK1 (IC50=0.23 μM). MRT00033659, a pyrazolo-pyridine analogue, induces p53 pathway activation and E2F-1 destabilisation.
    MRT00033659
  • HY-W340839
    p53-MDM2-IN-1
    		Inhibitor 99.91%
    p53-MDM2-IN-1 (Example 30) is an inhibitor of p53-MDM2/X protein interaction with an Ki value of 23.35 µM. p53-MDM2-IN-1 can be used for anti-tumor research.
    p53-MDM2-IN-1
  • HY-N1524
    Quinovic acid
    		p53 Inhibitor
    Quinovic acid is triterpene. Quinovic acid can ameliorate the Amyloid-β burden, p53 expression and cholesterol accumulation by deterring the oxidative stress through upregulating the Nrf2/HO-1 pathway. Quinovic acid can induce cancer cells apoptosis by upregulating death receptor 5 (DR5). Quinovic acid can be used for the researches of cancer, inflammation, metabolic and neurological disease, such as lung cancer and Alzheimer’s disease (AD).
    Quinovic acid
  • HY-174371
    INNO-220
    		Activator 98.60%
    INNO-220 is an orally active, CRBN-dependent molecular glue degrader targeting CK1α. INNO-220 induces cell cycle arrest at G0/G1 phase and triggers apoptosis by degrading CK1α. INNO-220 disrupts the assembly and function of the CARD11/BCL10/MALT1 complex, thereby inhibiting NF-κB signaling in stimulated T cells and lymphoma cells that harbor an activating mutation in CARD11. INNO-220 provides a new direction for lymphoma research.
    INNO-220
  • HY-W281364
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine
    		99.9%
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine is a mutagenic compound.
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine
  • 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-169240
    MX69-102
    		Activator 99.44%
    MX69-102 (compound MX69-102) is an MDM-2/p53 inhibitor, inducing MDM2 degradation, resulting in p53 activation and cancer cell apoptosis. MX69-102 shows effective inhibition on xenografted human MDM2-overexpressing ALL in SCID mice..
    MX69-102
  • 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-W718423
    Isodecyl diphenyl phosphate
    		Activator 99.40%
    Isodecyl diphenyl phosphate (IDPP) is a flame retardant. Isodecyl diphenyl phosphate induces cytotoxicity, DNA damage, mitochondrial dysfunction and oxidative stress in cancer cells, and mediates DNA damage and cell cycle arrest via a p53-dependent pathway.
    Isodecyl diphenyl phosphate
  • HY-15954B
    NVP-CGM097 sulfate
    		MDM2 Inhibitor 98.82%
    NVP-CGM097 sulfate is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.
    NVP-CGM097 sulfate
  • HY-18658A
    Siremadlin (R Enantiomer)
    		Control 99.19%
    Siremadlin R Enantiomer (NVP-HDM201 R Enantiomer) is the R enantiomer of Siremadlin. Siremadlin is a potent and highly specific MDM-2/p53 inhibitor.
    Siremadlin (R Enantiomer)
  • HY-B0960S
    Sulfabenzamide-d4
    		99.74%
    Sulfabenzamide (N-Sulfanilylbenzamide)-d4 is the deuterium labeled Sulfabenzamide (HY-B0960). Sulfabenzamide is a sulfonamide antibacterial agent. Sulfabenzamide exhibit antibacterial activity against Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 8739). Sulfabenzamide can promote autophagic cell autophagy in breast cancer cells through p53/ DRAM pathway. Sulfabenzamide increases caspase-3 activity, deactivates PARP1 and DNA-PK, downregulates AKT1 and AKT2. Sulfabenzamide can be used for the researches of breast cancer and bacterial infections.
    Sulfabenzamide-d<sub>4</sub>
  • HY-16138
    Ivaltinostat
    		Activator 99.70%
    Ivaltinostat (CG-200745) is an orally active, potent pan-HDAC inhibitor which has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. Ivaltinostat inhibits deacetylation of histone H3 and tubulin. Ivaltinostat induces the accumulation of p53, promotes p53-dependent transactivation, and enhances the expression of MDM2 and p21 (Waf1/Cip1) proteins. Ivaltinostat enhances the sensitivity of Gemcitabine-resistant cells to Gemcitabine (HY-16138) and 5-Fluorouracil (5-FU; HY-90006). Ivaltinostat induces apoptosis and has anti-tumour effects.
    Ivaltinostat
Cat. No. Product Name / Synonyms Application Reactivity
All Rights Reserved.
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.