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-16138
    Ivaltinostat
    		Activator
    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
  • HY-145785
    ADH-6
    		Modulator
    ADH-6 is a tripyridylamide compound. ADH-6 abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. ADH-6 has the potential for the research of cancer diseases[1].
    ADH-6
  • HY-125858A
    MI-1061 TFA
    		Inhibitor
    MI-1061 TFA is a potent, orally bioavailable, and chemically stable MDM2 (MDM2-p53 interaction) inhibitor (IC50=4.4 nM; Ki=0.16 nM). MI-1061 TFA potently activates p53 and induces apoptosis in the SJSA-1 xenograft tumor tissue in mice. Anti-tumor activity.
    MI-1061 TFA
  • HY-155974
    MeOIstPyrd
    		Activator 99.84%
    MeOIstPyrd is an anti-skin cancer agent. MeOIstPyrd inhibits cell proliferation, migration, and spheroid formation by activating the mitochondrial intrinsic apoptotic pathway. MeOIstPyrd induces DNA damage. MeOIstPyrd activates p53, and increases the half-life of p53 and stabilizes p53 by phosphorylating it at ser15. MeOIstPyrd binds to MDM2 in the p53 sub-pocket and blocks p53-MDM2 interaction.
    MeOIstPyrd
  • HY-123929
    PAWI-2
    		Activator 99.29%
    PAWI-2 is a p53-Activator and Wnt Inhibitor. PAWI-2 inhibits β3-KRAS signaling independent of KRAS. PAWI-2 selectively inhibits phosphorylation of TBK1. PAWI-2 activates apoptosis (activation of caspase-3/7), and induces PARP cleavage. PAWI-2 promotes optineurin translocation into the nucleus and causes G2/M arrest. PAWI-2 reverses cancer stemness and overcomes drug resistance in an integrin β3 KRAS-dependent human pancreatic cancer stem cells (hPCSCs). PAWI-2 inhibits growth of tumors from hPCSCs in orthopic xenograft mice model.
    PAWI-2
  • HY-162410
    Fluplatin
    		Inhibitor
    Fluplatin is a prodrug composed of cisplatin and fluvastatin. Fluplatin has antitumor activity.
    Fluplatin
  • HY-14967
    NSC 66811
    		p53 Activator 98.12%
    NSC 66811 is a MDM2-p53 inhibitor, with a Ki of 120 nM for binding to MDM2.
    NSC 66811
  • HY-144105
    NSC405640
    		Inhibitor 98.0%
    NSC405640 is a potent inhibitor of the MDM2-p53 interaction. NSC405640 rescues structural p53 mutations. NSC405640 selectively inhibits the growth of cell lines with wild-type p53.
    NSC405640
  • HY-151883
    APE1-IN-2
    		p53 Activator 98.28%
    APE1-IN-2 (compound AP1) is a Pt(IV) proagent, targeting a critical BER protein, apurinic/apyrimidinic endonuclease 1 (APE1). APE1-IN-2 shows anticancer activity. APE1-IN-2 induces intracellular accumulation of platinum and activates DNA damage response and apoptosis signals.
    APE1-IN-2
  • 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-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-A0280
    Roslin 2 bromide
    		Activator 99.0%
    Roslin 2 bromide (Benzylhexamethylenetetramine bromide) is a p53 reactivator with anticancer effects. Roslin 2 bromide binds FAK, disrupts the binding of FAK and p53.
    Roslin 2 bromide
  • HY-W281364
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine is a mutagenic compound.
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine
  • HY-171499
    Cenersen
    		Inhibitor
    Cenersen (EL625) is an oligonucleotide targeting TP53. Cenersen can eliminate the activity of TP53 gain-of-function mutants and increase the sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. Cenersen can be used for the study of chronic lymphocytic leukemia (CLL).
    Cenersen
  • HY-70027
    p53 and MDM2 proteins-interaction-inhibitor (chiral)
    		MDM2 Inhibitor 98.13%
    p53 and MDM2 proteins-interaction-inhibitor (chiral) (Compound 32) is an inhibitor of the interaction between p53 and MDM2 proteins.
    p53 and MDM2 proteins-interaction-inhibitor (chiral)
  • HY-B0774R
    Seratrodast (Standard)
    		Inhibitor
    Seratrodast (Standard) is the analytical standard of Seratrodast. This product is intended for research and analytical applications. Seratrodast (AA 2414), an orally active antiasthmatic agent, is a thromboxane A2 receptor (TP) antagonist and ferroptosis inhibitor. Seratrodast reduces lipid ROS production, modulates the systemic xc-/GSH/GPX4 axis, and inhibits JNK phosphorylation and p53 expression. Seratrodast exhibits anti-asthmatic and anti-epileptic activity.
    Seratrodast (Standard)
  • HY-W654013
    Minocycline-d7
    		p53 Activator
    Minocycline-d7 is deuterium labeled Minocycline. 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>7</sub>
  • HY-120667
    DS-5272
    		Inhibitor
    DS-5272 is an orally acitve inhibitor for p53-MDM2 with an IC50 of 20 nM. DS-5272 inhibits the proliferation of SJSA-1 (wildtype p53, IC50=0.17 μM) and DLD-1 (mutant p53). DS-5272 arrest the cell cycle, and induces apoptosis in SJSA-1. DS-5272 exhibits antitumor efficacy in mice.
    DS-5272
  • HY-163083
    JN122
    		Inhibitor
    JN122, a spiroindoline-containing molecule, is a MDM2 inhibitor. JN122 Inhibits MDM2/p53 protein–protein interaction and exerts robust in vivo antitumor efficacy. JN122 has antiproliferative activity in HCT-116 cells and HEK-293 cells with IC50 values of 39.6 nM and 4.28μM, respectively. JN122 can promote activation of p53 and its target genes, inhibited cell cycle progression, and induced cell apoptosis.
    JN122
  • HY-139846
    MK-4688
    		Inhibitor
    MK-4688 is an efficient inhibitor of the HDM2-p53 protein-protein interaction.
    MK-4688
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.