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-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-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-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-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-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-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-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-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-P3509A
    PNC-28 acetate
    		99.95%
    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-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-W011434
    Triglycidyl isocyanurate
    		p53 Activator ≥98.0%
    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-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-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-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-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-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
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.