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-138054
    Cjoc42
    		99.0%
    Cjoc42 is a compound capable of binding to gankyrin. Cjoc42 inhibits gankyrin activity in a dose-dependent manner. Cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin. Cjoc42 restores p53-dependent transcription and sensitivity to DNA damage.
    Cjoc42
  • HY-10412
    CEP-1347
    		p53 Activator 98.50%
    CEP-1347 is an inhibitor of the JNK/SAPK pathway with neuroprotective effects. CEP-1347 blocks JNK1 activation induced by members of the mixed lineage kinase (MLK) family (MLK3, MLK2, MLK1, dual leucine zipper kinase, and leucine zipper kinase). As an inhibitor of MDM4, CEP-1347 can more effectively inhibit the growth of glioma cells expressing wild-type p53.
    CEP-1347
  • HY-145759
    Mutant p53 modulator-1
    		Modulator 99.89%
    Mutant p53 modulator-1 is a mutant p53 modulator. Mutant p53 modulator-1 reduces the progression of cancers that contain a p53 mutation (extracted from patent WO2021231474A1, compound 231B).
    Mutant p53 modulator-1
  • HY-N1931
    Epifriedelanol
    		99.69%
    Epifriedelanol is a triterpenoid found in the root bark of Ulmus davidiana. Epifriedelanol induces apoptosis in DU145 cells. Epifriedelanol has antitumor and anti-inflammatory activities. Epifriedelanol inhibits cellular senescence in human primary cells.
    Epifriedelanol
  • HY-148833
    MDM2-p53-IN-16
    		Inhibitor 99.08%
    MDM2-p53-IN-16 is a MDM2-p53 complex inhibitor with an IC50 value of 4.3 nM to dissociate human p53/MDM2 complex. MDM2-p53-IN-16 reactivates p53, and induces Glioblastoma Multiforme (GBM) cell apoptosis and cell-cycle arrest. MDM2-p53-IN-16 can be used for the cancer research.
    MDM2-p53-IN-16
  • 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-15676A
    Idasanutlin (enantiomer)
    		Control 99.18%
    Idasanutlin enantiomer is the isomer of Idasanutlin (HY-15676), and can be used as an experimental control. Idasanutlin (RG7388) is a potent and selective MDM2 antagonist, inhibiting p53-MDM2 binding, with an IC50 of 6 nM.
    Idasanutlin (enantiomer)
  • HY-P2096
    Hexapeptide-11
    		Inhibitor 99.77%
    Hexapeptide-11 is an anti-aging peptide that can protect fibroblasts from premature cell senescence mediated by oxidative stress. Hexapeptide-11 is also a potential stimulator of hyaluronic acid in keratinocytes, and can enhance skin barrier function by upregulating the expression of HAS2 and EGR3, and downregulating the expression of HYAL2. Hexapeptide-11 can also improve skin elasticity.
    Hexapeptide-11
  • HY-U00447
    PK11000
    		p53 Activator 99.56%
    PK11000 is an alkylating agent, and stabilizes the DNA-binding domain of both WT and mutant p53 proteins by covalent cysteine modification without compromising DNA binding. PK11000 has anti-tumor activities.
    PK11000
  • HY-P3508A
    PNC-27 acetate
    		99.32%
    PNC-27 acetate, a chimeric p53-penetratin peptide binds to HDM-2 in a p53 peptide-like structure, induces selective membrane-pore formation and leads to cancer cell lysis. PNC-27 acetate is an anticancer peptide. PNC-27 acetate can be used in acute myeloid leukemia research.
    PNC-27 acetate
  • HY-101266B
    Milademetan tosylate hydrate
    		MDM2 Inhibitor 98.89%
    Milademetan (DS-3032) tosylate hydrate is a specific and orally active MDM2 inhibitor for the research of acute myeloid leukemia (AML) or solid tumors. Milademetan (DS-3032) tosylate hydrate induces G1 cell cycle arrest, senescence and apoptosis.
    Milademetan tosylate hydrate
  • HY-128840
    PROTAC MDM2 Degrader-1
    		MDM2 Inhibitor 98.11%
    PROTAC MDM2 Degrader-1 (Compound 15a) is a MDM2 PROTAC degrader. The structures of both Linker ends of PROTAC MDM2 Degrader-1 are MDM2 ligands. PROTAC MDM2 Degrader-1 can not only block the binding of p53-MDM2, but also degrade the target MDM2 protein by utilizing the function of the E3 ligase of MDM2 itself, thus exerting an anti-tumor effect. (Pink: MDM2 ligand 2 (HY-128836); Black: Linker (HY-128844); Blue: E3 ligase Ligand 15 (HY-128836))
    PROTAC MDM2 Degrader-1
  • HY-103640
    Amifostine thiol dihydrochloride
    		p53 Activator 99.16%
    Amifostine thiol (WR-1065) dihydrochloride can protect normal tissues from the toxic effects of certain cancer agents and activate p53 through a JNK-dependent signaling pathway.
    Amifostine thiol dihydrochloride
  • HY-176083
    ASTX295
    		Antagonist 99.81%
    ASTX295 is a selective mouse double minute 2 (MDM2) antagonist with an IC50 value of <1 nM. ASTX295 specifically blocks the interaction between MDM2 and p53, reactivating wild-type (WT) TP53, and then inducing the expression of related transcriptional targets, leading to cell death and cell cycle arrest. ASTX295 is promising for research of lymphoid malignancies, such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and T-cell lymphoma.
    ASTX295
  • HY-108636
    RETRA
    		p53 Activator 99.42%
    RETRA is a mutant p53-dependent activator of p73 that suppresses mutant p53-bearing cancer cells. RETRA increases the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects.
    RETRA
  • HY-N8210
    Homoeriodictyol
    		Agonist 99.83%
    Homoeriodictyol is an orally active, bitter-tasting flavanone that can penetrate the blood-brain barrier. Homoeriodictyol enhances synaptic-related protein expression through NCOA4-mediated ferritin autophagy. Homoeriodictyol improves memory impairment in mice by inhibiting the NLRP3 inflammasome. Homoeriodictyol protects human endothelial cells from oxidative damage by activating Nrf2 and inhibiting mitochondrial dysfunction. Homoeriodictyol enhances ROS activity and induces apoptosis, exhibiting anticancer effects. Homoeriodictyol inhibits the survival and migration of androgen-resistant prostate cancer cells in vitro. Homoeriodictyol exerts antinociceptive activity in mice in vivo.
    Homoeriodictyol
  • HY-P3509A
    PNC-28 acetate
    		98.79%
    PNC-28 acetate 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 acetate can be used for pancreatic cancer research.
    PNC-28 acetate
  • HY-15035
    S-Diclofenac
    		Activator 99.20%
    S-Diclofenac (ACS 15) is a hybrid molecule of an H2S donor and the NSAID diclofenac. S-Diclofenac activates the p53 signaling pathway, and inhibits the activation of JNK. S-Diclofenac exhibits antioxidant and anti-inflammatory activities.
    S-Diclofenac
  • HY-108637A
    PhiKan 083 hydrochloride
    		p53 Activator 99.27%
    PhiKan 083 hydrochloride is a carbazole derivative, which binds to the surface cavity and stabilizes Y220C (a p53 mutant), with a Kd of 167 μM, and a relative binding affinity (Kd) of 150 μM in Ln229 cells.
    PhiKan 083 hydrochloride
  • HY-N2993
    Polyporenic acid C
    		Activator 99.80%
    Polyporenic acid C is a lanostane-type triterpenoid. Polyporenic acid C can be isolated from Poria cocos. Polyporenic acid C causes the cleavage of caspase-8 and caspase-3, as well as the cleavage of PARP. Polyporenic acid C reduces the phosphorylation level of Akt (Ser473), increases the phosphorylation of PTEN and p53 (Ser15), and activates JNK. Polyporenic acid C induces Apoptosis. Polyporenic acid C shows anticancer activity against non-small cell lung cancer.
    Polyporenic acid C
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.