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-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-119014
    NU-8231
    		Inhibitor
    NU-8231 (Compound 2) is a p53-MDM2 binding inhibitor with an IC50 of 5.3-200 μM for inhibiting the p53-MDM2 interaction. NU-8231 is applicable for cancer research.
    NU-8231
  • 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-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-19980G
    Eprenetapopt (GMP)
    		p53 Activator
    Eprenetapopt (GMP) (APR-246(GMP)) is Eprenetapopt (HY-19980) in GMP grade. GMP small molecules works appropriately as an auxiliary reagent for cell therapy manufacture. Eprenetapopt (APR-246) is a first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. Eprenetapopt triggers apoptosis in tumor cells. Eprenetapopt also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance.
    Eprenetapopt (GMP)
  • 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-12737
    AM-6761
    		MDM2 Inhibitor
    AM-6761 is a potent MDM2 inhibitor with an IC50 of 0.1 nM.
    AM-6761
  • 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-180618
    p53 DUBTAC modulator-1
    		Activator
    p53 DUBTAC modulator-1 (Compound A1) is a p53 Y220C DUBTAC modulator (Kd = 12.09 µM). p53 DUBTAC modulator-1 effectively reactivates and deubiquitinates mutant p53 Y220C. p53 DUBTAC modulator-1 upregulates p53 Y220C protein levels. p53 DUBTAC modulator-1 induces Apoptosis, reduces Bcl-2, inhibits Wnt signaling. p53 DUBTAC modulator-1 has anti-cancer activity against liver cancer.
    p53 DUBTAC modulator-1
  • 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-P11490
    DPMI-ω
    		Antagonist
    DPMI-ω is a dual-specificity d-peptide antagonist of oncogenic proteins MDM2 and MDMX. DPMI-ω, upon fabrication on gold nanoparticles, efficiently traverses tumor cells and kills them by reactivating the p53 signaling pathway. DPMI-ω can disrupte the p53-MDM2/MDMX complex. DPMI-ω can inhibit B16 melanoma growth and induce cells G0/G1 phase arrest. DPMI-ω can augment the efficacy of immunotherapy by expanding CD3+/CD8+ cytotoxic T cells and suppressing CD4+/CD25+ regulatory T cells companied with anti-PD1 antibody. DPMI-ω can be used for research of melanoma.
    DPMI-ω
  • HY-15840A
    (E/Z)-YLF-466D
    		Activator
    (E/Z)-YLF-466D (E/Z)-C24) is a AMPK activator. (E/Z)-YLF-466D directly activates AMPK, a key regulator of energy homeostasis. (E/Z)-YLF-466D activates p53 and regulates proliferation signaling pathways in cancer cells. (E/Z)-YLF-466D exhibits anti-tumor activity.
    (E/Z)-YLF-466D
  • HY-182016
    PROTAC ATR degrader-3
    PROTAC ATR degrader-3 is a potent CRBN-based ATR PROTAC degrader with a DC50 of 127 nM. PROTAC ATR degrader-3 also degrades CHK1 with an DC50 of 135 nM. PROTAC ATR degrader-3 inhibits cancer cells proliferation, migration and invasion, triggers apoptosis and induces S phase arrest and DNA damage. PROTAC ATR degrader-3 achieves tumor growth inhibition in LoVo xenograft mouse model without apparent toxicity. PROTAC ATR degrader-3 can be used for the research of colorectal cancer.
    PROTAC ATR degrader-3
  • HY-W710827
    N,N'-Methylenebisacrylamide-d6
    N,N'-Methylenebisacrylamide-d6 is the deuterium labeled N,N'-Methylenebisacrylamide (HY-D0848). N,N'-Methylenebisacrylamide (Bisacrylamide) is an orally active acrylamide dimer and crosslinker. N,N'-Methylenebisacrylamide increases CYP2E1, P53, cleaved caspase-3. N,N'-Methylenebisacrylamide promotes hepatic cancer. N,N'-Methylenebisacrylamide changes sperm abnormality rate and sperm count. N,N'-Methylenebisacrylamide decreases the number of various cells in the blood as well as induces liver and testicular damage. N,N'-Methylenebisacrylamide is used to prepare polyacrylamide gel.
    N,N'-Methylenebisacrylamide-d<sub>6</sub>
  • 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-186051
    Rezatapopt analog-2
    		Ligand
    Rezatapopt analog-2 (compound A-15) is an analog of Rezatapopt (HY-156633) and can bind to P53.
    Rezatapopt analog-2
  • HY-115797
    LQFM030
    		Inhibitor
    LQFM030 is a novel small molecule MDM2 inhibitor. LQFM030 exhibits concentration dependent cytotoxicity in K562 cells (IC50 = 0.28 mM). LQFM030 induces cell apoptosis through G0/G1 phase cell cycle arrest and increased Caspase activity. LQFM030 downregulates the mRNA expression of MDM2, MDMX, p73, MYC, and NF-κB. LQFM030 is commonly used in research on cancers such as leukemia.
    LQFM030
  • HY-180509
    Topoisomerase I/IIα-IN-1
    		Inhibitor
    Topoisomerase I/IIα-IN-1 (Compound 20i) is a Topoisomerase I/IIα inhibitor. MDM2-IN-27 can effectively block the inhibitory effect of MDM2 on p53, thereby activating the p53 pathway. MDM2-IN-27 has relatively poor anti-proliferative activity against breast cancer, colon cancer, and cutaneous squamous cell carcinoma.
    Topoisomerase I/IIα-IN-1
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.