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-128784
    PK11007
    		p53 Activator 98.72%
    PK11007 is a mild thiol alkylator with anticancer activity. PK11007 stabilizes p53 via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. PK11007 induces mutant p53 cancer cell death by increasing reactive oxygen species (ROS) levels.
    PK11007
  • HY-W042191
    Oxychlororaphine
    		Inducer 98.90%
    Oxychloroaphine could be isolated from the bacterium Pantoea agglomerans naturally present in soil. Oxychloroaphine has broad-spectrum antifungal activity. Oxychloroaphine has cytotoxicity in a dose-dependent manner and induces apoptosis. Oxychloroaphine can be used in research of cancer.
    Oxychlororaphine
  • HY-134823
    MD-222
    		MDM2 Inhibitor 99.81%
    MD-222 is the first-in-class highly potent PROTAC degrader of MDM2. MD-222 consists of ligands for Cereblon and MDM2. MD-222 induces rapid degradation of the MDM2 protein and activation of wild-type p53 in cells. MD-222 has anticancer effects.
    MD-222
  • HY-15335
    Nutlin-3b
    		MDM2 Inhibitor 99.16%
    Nutlin-3b is a p53/MDM2 inhibitor with an IC50 of 13.6 μM. Nutlin-3b is 150 times less potent in binding to MDM2 than Nutlin-3a.
    Nutlin-3b
  • HY-108638
    NSC 146109 hydrochloride
    		p53 Activator 99.60%
    NSC 146109 hydrochloride is a small-molecule p53 activator that target MDMX and can be used for breast cancer research. NSC 146109 hydrochloride is a pseudourea derivative, promotes breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes.
    NSC 146109 hydrochloride
  • HY-152859
    Brigimadlin
    		MDM2 Inhibitor 98.96%
    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-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-101266B
    Milademetan tosylate hydrate
    		MDM2 Inhibitor 98.18%
    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-128842
    PROTAC MDM2 Degrader-3
    		MDM2 Inhibitor
    PROTAC MDM2 Degrader-3 is a MDM2 degrader based on PROTAC technology. PROTAC MDM2 Degrader-3 composes of a potent MDM2 inhibitor, linker, and the MDM2 ligand for E3 ubiquitin ligase.
    PROTAC MDM2 Degrader-3
  • HY-100892
    MX69
    		MDM2 Inhibitor 99.60%
    MX69 is an inhibitor of MDM2/XIAP, used for cancer treatment.
    MX69
  • HY-148369
    U7D-1
    		p53 Activator 99.65%
    U7D-1 is a first-in-class potent and selective USP7 (ubiquitin-specific protease 7) PROTAC degrader, with a DC50 of 33 nM in RS4;11 cells. U7D-1 shows anticancer activity. U7D-1 induces apoptosis in Jeko-1 cells.
    U7D-1
  • HY-100475
    KYP-2047
    		p53 Activator 99.68%
    KYP-2047 is a potent and BBB-penetrating prolyl-oligopeptidase (POP) inhibitor, with an Ki value of 0.023 nM. KYP-2047 reduces glioblastoma proliferation through angiogenesis and apoptosis modulation.
    KYP-2047
  • HY-15221
    Methylstat
    		Inducer 98.34%
    Methylstat is a potent histone demethylases inhibitor. Methylstat shows anti-proliferative activity with low cytotoxicity. Methylstat induces apoptosis and cell cycle arrest at G0/G1 phase. Methylstat increases the expression of p53 and p21 protein levels. Methylstat inhibits angiogenesis induced by various cytokines. Methylstat can be used as a chemical probe for addressing its role in angiogenesis.
    Methylstat
  • HY-103640
    Amifostine thiol dihydrochloride
    		p53 Activator
    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-130684
    MDM2-IN-1
    		MDM2 Inhibitor 99.06%
    MDM2-IN-1 (Compound 30) is a synthetic MDM2-p53 interaction (MDM2) inhibitor and contains the trans (D-)configuration.
    MDM2-IN-1
  • HY-W001538
    S-Propargylcysteine
    		Inducer
    S-Propargylcysteine (SPRC), a structural analog of S-allyl cysteine (SAC), is a slow H2S-releasing compound. S-Propargylcysteine reduces Ca2+ accumulation and inflammatory cytokines, inhibits STAT3, and elevates p53 and Bax. S-Propargylcysteine has anti-inflammatory activity and protects mice against acute pancreatitis. S-Propargylcysteine also has cardioprotective, neuroprotective acitivties.
    S-Propargylcysteine
  • 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-120086
    RO-5963
    		MDM2 Inhibitor 99.97%
    RO-5963 is a dual p53-MDM2 and p53-MDMX inhibitor with IC50s of ~17 nM and ~24 nM, respectively.
    RO-5963
  • HY-145937
    PK9327
    		Modulator 98.50%
    PK9327 is a small-molecule stabilizer targeting cavity-creating p53 cancer mutations.
    PK9327
  • HY-15510B
    Tenovin-6 Hydrochloride
    		p53 Activator ≥98.0%
    Tenovin-6 Hydrochloride, an analog of Tenovin-1 (HY-13423), is an activator of p53 transcriptional activity. Tenovin-6 Hydrochloride inhibits the protein deacetylase activities of purified human SIRT1, SIRT2, and SIRT3 with IC50s of 21 μM, 10 μM, and 67 μM, respectively. Tenovin-6 Hydrochloride also inhibits dihydroorotate dehydrogenase (DHODH).
    Tenovin-6 Hydrochloride
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.