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-101266
    Milademetan
    		MDM2 Inhibitor 98.87%
    Milademetan (DS-3032) is a specific and orally active MDM2 inhibitor for the research of acute myeloid leukemia (AML) or solid tumors. Milademetan (DS-3032) induces G1 cell cycle arrest, senescence and apoptosis.
    Milademetan
  • HY-156633
    Rezatapopt
    		p53 Activator 99.78%
    Rezatapopt (PC14586) is an orally active antineoplastic agent. Rezatapopt binds to a pocket created by the TP53 Y220C mutation. Rezatapopt restores p53 tumor suppressor functions by stabilization of the p53 protein structure. Rezatapopt demonstrates tumor inhibition and regression in mouse models with established human tumor xenografts harboring the TP53 Y220C mutation.
    Rezatapopt
  • HY-108521
    HX531
    		Activator 99.87%
    HX531 is an orally active RXR antagonist with an IC50 of 18 nM. HX531 upregulates the p53-p21Cip1 pathway. HX531 abrogates the anti-apoptotic effect of t-RA. HX531 exerts anti-obesity, anti-diabetic and anti-melanoma activities.
    HX531
  • HY-18634
    NSC319726
    		p53 Activator 99.60%
    NSC319726 (ZMC1) is a mutant p53R175 reactivator; inhibits growth of fibroblasts expressing the p53R175 mutation (IC50 = 8 nM); shows no inhibition for p53 wild-type cells.
    NSC319726
  • HY-10959
    RG7112
    		MDM2 Inhibitor 99.91%
    RG7112 is a potent, selective, first clinical, orally active and blood-brain barrier crossed MDM2-p53 inhibitor, with an IC50 of 18 nM and a KD of 11 nM for binding to MDM2.
    RG7112
  • HY-101518
    Alrizomadlin
    		MDM2 Inhibitor 98.67%
    Alrizomadlin (APG-115) is an orally active MDM2 protein inhibitor binding to MDM2 protein with IC50 and Ki values of 3.8 nM and 1 nM, respectively. Alrizomadlin blocks the interaction of MDM2 and p53 and induces cell-cycle arrest and apoptosis in a p53-dependent manner.
    Alrizomadlin
  • HY-123076
    Pifithrin-α, p-Nitro, Cyclic
    		p53 Inhibitor 99.73%
    Pifithrin-α, p-Nitro, Cyclic (PFN-α) is cell-permeable and active-form p53 inhibitor. Pifithrin-α, p-Nitro, Cyclic is one order magnitude more active than Pifithrin-α in protecting cortical neurons exposed to Etoposide (ED50=30 nM). Pifithrin-α, p-Nitro, Cyclic behaves as a p53 posttranscriptional activity inhibitor. Pifithrin-α, p-Nitro, Cyclic do not prevent p53 phosphorylation on the S15 residue.
    Pifithrin-α, p-Nitro, Cyclic
  • HY-P4210
    Sulanemadlin
    		Inhibitor
    Sulanemadlin (ALRN-6924) is a potent and cell-permeating p53-based peptidomimetic macrocycles. Sulanemadlin is a inhibitor of the p53-MDM2, p53-MDMX, or both p53 and MDM2 and MDMX protein-protein interactions. Sulanemadlin can be used for cancers research.
    Sulanemadlin
  • HY-18935
    CBL0137
    		Activator 99.68%
    CBL0137, a curaxin compound, is a histone chaperone facilitates chromatin transcription (FACT) inhibitor. CBL0137 downregulates NF-?B and activates p53. CBL0137 restores both histone H3 acetylation and trimethylation. CBL0137 is an anticancer agent. CBL0137 induces cancer cell apoptosis.
    CBL0137
  • HY-18935
    CBL0137
    		p53 Activator 99.68%
    CBL0137, a curaxin compound, is a histone chaperone facilitates chromatin transcription (FACT) inhibitor. CBL0137 downregulates NF-?B and activates p53. CBL0137 restores both histone H3 acetylation and trimethylation. CBL0137 is an anticancer agent. CBL0137 induces cancer cell apoptosis.
    CBL0137
  • HY-13424
    RITA
    		p53 Activator 98.77%
    RITA is an inhibitor of p53-HDM-2 interaction, binds to p53dN, with a Kd of 1.5 nM, and also induces DNA-DNA cross-links.
    RITA
  • HY-N7264
    7α-Hydroxycholesterol
    		99.99%
    7α-Hydroxycholesterol is a cholesterol oxide and can serve as a biomarker for oxidative stress and lipid peroxidation. 7α-Hydroxycholesterol has cytotoxic and pro-inflammatory activities. 7α-Hydroxycholesterol can also inhibit sterol synthesis and reduce the activity of HMG-CoA reductase. 7α-Hydroxycholesterol can be used in the research of diseases such as diabetes and atherosclerosis.
    7α-Hydroxycholesterol
  • HY-16702A
    Pifithrin-β hydrobromide
    		p53 Inhibitor 99.97%
    Pifithrin-β hydrobromide (PFT β hydrobromide) is a potent p53 inhibitor with an IC50 of 23 μM.
    Pifithrin-β hydrobromide
  • HY-152859
    Brigimadlin
    		MDM2 Inhibitor 99.72%
    Brigimadlin (BI 907828) is an orally active E3 ubiquitin-protein ligase MDM-2 inhibitor, preventing MDM-2 from negatively regulating the tumor suppressor p53. Brigimadlin can be used for antineoplastic research.
    Brigimadlin
  • HY-N2037A
    Higenamine hydrochloride
    		Activator 99.68%
    Higenamine hydrochloride is a selective LSD1 inhibitor (IC50=1.47 μM) that can be isolated from aconite. Higenamine hydrochloride has anti-inflammatory and antibacterial activity. Higenamine (Norcoclaurine) can attenuate IL-1β-induced Apoptosis through ROS-mediated PI3K/Akt signaling pathway. Higenamine hydrochloride protects brain cells from oxygen deprivation. Higenamine can promote bone formation in osteoporosis through the SMAD2/3 pathway. Higenamine hydrochloride can be used to study cancer, inflammation, cardiorenal syndrome and other diseases.
    Higenamine hydrochloride
  • HY-152860
    Darizmetinib
    		Inhibitor 99.94%
    Darizmetinib (HRX-0215) is an orally active, potent and selective inhibitor of mitogen-activated protein kinase kinase 4 (MKK4). Darizmetinib leads to enhancement of the MKK7 and JNK1 signaling pathways, thereby activating the transcription factors ATF2 and ELK1, promoting cell proliferation and liver regeneration. Darizmetinib is promising for research of preventing liver failure after extensive oncological liver resections or transplantation of small liver grafts.
    Darizmetinib
  • HY-19896
    COTI-2
    		p53 Activator 99.66%
    COTI-2, an anti-cancer agent with low toxicity, is an orally available third generation activator of p53 mutant forms. COTI-2 acts both by reactivating mutant p53 and inhibiting the PI3K/AKT/mTOR pathway. COTI-2 induces apoptosis in multiple human tumor cell lines. COTI-2 exhibits antitumor activity in HNSCC through p53-dependent and -independent mechanisms. COTI-2 converts mutant p53 to wild-type conformation.
    COTI-2
  • HY-16271
    Kevetrin hydrochloride
    		p53 Activator ≥98.0%
    Kevetrin hydrochloride is a potent activator of p53, induces apoptosis in TP53 wild-type and mutant acute myeloid leukemia cells. Kevetrin a preferential cytotoxic activity against blast cells.
    Kevetrin hydrochloride
  • HY-P4157
    FOXO4-DRI
    		Inhibitor 99.93%
    FOXO4-DRI is a cell-permeable peptide antagonist that blocks the interaction of FOXO4 and p53. FOXO4-DRI is a senolytic peptide that induces apoptosis of senescent cells.
    FOXO4-DRI
  • HY-148416
    p53 Activator 7
    		p53 Activator 98.52%
    p53 Activator 7 is a p53 mutation Y220C (MDM-2/p53) activator with an EC50 of 104 nM. p53 Activator 7 can bind to p53 mutant and restore its ability to bind DNA (WO2022213975A1; Example B-1). p53 Activator 7 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 7
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.