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-W011434R
    Triglycidyl isocyanurate (Standard)
    		p53 Activator
    Triglycidyl isocyanurate (Standard) is the analytical standard of Triglycidyl isocyanurate. This product is intended for research and analytical applications. 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 (Standard)
  • HY-144792
    Bcl-2-IN-7
    		p53 Activator
    Bcl-2-IN-7 (compound 6) is a potent Bcl-2 (B-cell lymphoma-2) inhibitor. Bcl-2-IN-7 down-regulates the expression of Bcl-2, and increases the expression of p53, Bax, and caspase-7 mRNA. Bcl-2-IN-7 induces cell cycle arrest and apoptosis in breast cancer MCF-7 cells. Bcl-2-IN-7 shows good anticancer activity, with IC50 values of 20.17, 22.64, 45.57, and 51.50 μM against MCF-7, LoVo, HepG2, and A549 cell lines, respectively.
    Bcl-2-IN-7
  • HY-169688
    NA-17
    		Activator
    NA-17 is a naphthalimide compound with anti-tumor activity and lower toxicity to normal cells like HL-7702 and WI-38. NA-17 exhibits a p53-dependent selective inhibition in various NSCLC cells, inducing the accumulation of active p53 in the mitochondria and nuclei of NSCLC cells. NA-17 can cause cell cycle arrest in the G1 phase, leading to apoptosis and cell death.
    NA-17
  • HY-126311
    4-Hydroxyresveratrol
    		Inducer
    4-Hydroxyresveratrol (3,4,5,4'-Tetrahydroxystibene), a Resveratrol (HY-16561) analog, differentially induces pro-apoptotic p53/Bax gene expression. 4-Hydroxyresveratrol induces apoptosis in SV40 virally transformed WI38 cells (WI38VA) cells, but not in WI38 cells. 4-Hydroxyresveratrol significantly induces the expression of p53, GADD45 and Bax genes and concomitantly suppresses the expression of bcl-2 gene in WI38VA.
    4-Hydroxyresveratrol
  • HY-P1755
    p53 (17-26)
    p53 (17-26) is amino acids 17 to 26 fragment of p53. p53 (17-26) is mdm-2-binding domain.
    p53 (17-26)
  • HY-155851
    Lepadin E
    		Activator
    Lepadin E is a significantly cytotoxic ferroptosis inducer that induces iron death through the classical p53-SLC7A11-GPX4 pathway. Lepadin E promoted p53 expression, decreases SLC7A11 and GPX4 levels, and leads to increased ROS and lipid peroxide production, and upregulated ACSL4 expression, thus causes cell death. Lepadin E has significant antitumor effect.
    Lepadin E
  • HY-120520
    Caylin-1
    		Inhibitor
    Caylin-1 is an inhibitor of MDM2 and an analog of Nutlin-3. Caylin-1 can bind to Bcl-XL and is used in multi-target anticancer research.
    Caylin-1
  • HY-P3509
    PNC-28
    PNC-28 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 can be used for pancreatic cancer research.
    PNC-28
  • HY-146095
    p53 Activator 2
    		p53 Activator
    p53 Activator 2 (compound 10ah) intercalats into DNA and results in significant DNA double-strand break.p53 Activator 2 increases the expression of p53, p-p53, CDK4, p21 to cause cell cycle arrest at G2/M phase.p53 Activator 2 induce apoptosis and significantly down-regulates the anti-apoptosis proteins Bcl-2, Bcl-xL and the levels of cyclin B1.p53 Activator 2 has anti-proliferation activity against MGC-803 cells, with an IC50 of 1.73 µM. p53 Activator 2 displays potent anticancer efficiency against MGC-803 xenograft tumors models.
    p53 Activator 2
  • HY-155571
    MDM2/XIAP-IN-3
    		Inhibitor
    MDM2/XIAP-IN-3 (compound 3e) is a dual MDM2/XIAP inhibitor. MDM2/XIAP-IN-3 reduces MDM2 and XIAP protein levels and increases p53 expression, thereby inhibiting cancer cell growth and causing cell death.
    MDM2/XIAP-IN-3
  • HY-115385R
    Lumichrome (Standard)
    		Activator
    Lumichrome (Standard) is the analytical standard of Lumichrome. This product is intended for research and analytical applications. Lumichrome, a photodegradation product of Riboflavin, is an endogenous compound in humans. Lumichrome inhibits human lung cancer cell growth and induces apoptosis via a p53-dependent mechanism. Lumichrom is the inhibitor for AKT/β-catenin signaling pathway. Lumichrom is the inhibitor for AKT/β-catenin signaling pathway.
    Lumichrome (Standard)
  • HY-170452
    MDM2 ligand 4
    		Ligand
    MDM2 ligand 4 is the ligand for MDM2 that can be used for synthesis of PROTAC degrader KT-253 (HY-170451).
    MDM2 ligand 4
  • HY-149911
    GY1-22
    		Inhibitor
    GY1-22 is an inhibitor of DNAJA1-mutP53R175H interacting pocket. GY1-22 can be used for the research of cancer.
    GY1-22
  • HY-158328A
    CA IX/VEGFR-2-IN-2
    		Activator
    CA IX/VEGFR-2-IN-2 (compound 5e) is a dual-targeted inhibitor. CA IX/VEGFR-2-IN-2 shows strong inhibitory effects on both CA IX (Ki=3.1 μM) and VEGFR-2 (IC50=32.1 nM). CA IX/VEGFR-2-IN-2 can be used for the study of pancreatic (PANC1), breast cancer (MCF7) and prostate cancer (PC3) .
    CA IX/VEGFR-2-IN-2
  • HY-P10295
    p53 (232-240)
    p53 (232-240) is a peptide segment of the 232-240 amino acid sequence of the human tumor suppressor protein p53. p53 (232-240) enhances its binding affinity to the Major histocompatibility complex (MHC), thereby enhancing the immunogenicity of this peptide to enhance the immune system's response to tumor antigens. p53 (232-240) can be used in the development of cancer vaccines and in the study of tumor cell recognition and clearance by the immune system.
    p53 (232-240)
  • HY-168623
    EGFR-IN-134
    		Activator
    EGFR-IN-134 (compound 3f), a triazolo[3,4-a]isoquinoline derivative, is a potent EGFR inhibitor with an IC50 of 0.023 µM. EGFR-IN-134 induces apoptosis and necrosis. EGFR-IN-134 initiates cell cycle arrest at the G2/M and pre-G1 phases, downregulates anti-apoptotic protein Bcl2 and upregulates pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. EGFR-IN-134 shows antiproliferative and anticancer activity.
    EGFR-IN-134
  • HY-119053
    MS7972
    		p53 Inhibitor 99.81%
    MS7972 is a small molecule that blocks human p53 and CREB binding protein association. MS7972 can almost completely block this BRD interaction at 50 μM.
    MS7972
  • HY-107466
    WK298
    WK298 is a potent inhibitor of the MDM2/MDMX-p53 interaction with good anti-tumor activity. WK298 can fully activate the p53 pathway by inhibiting the binding of MDM2 and MDMX to p53. The development of WK298 benefited from a deep understanding of the key elements of the p53-MDM2/MDMX interaction structure.
    WK298
  • HY-147783
    Anticancer agent 68
    Anticancer agent 68 is (Compound 12) is an anti-cancer agent. Anticancer agent 68 arrests the cells at the G2/M phase and induces programmed cell death. Anticancer agent 68 induces upregulation of tumor suppression via activation of p53 & PTEN.
    Anticancer agent 68
  • HY-169327
    MD-265
    		Degrader
    MD-265 is a PROTAC degrader that can break down MDM2, leading to activation of p53 in cancer cells carrying wild-type p53. MD-265 achieves complete tumor regression and improves long-term survival of mice with leukemia. (Pink: MI-1063 (HY-133754); Black: linker; Blue: Lenalidomide (HY-A0003).
    MD-265
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.