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-124072
    HL001
    		Modulator 98.90%
    HL001 is an orally active small molecule inhibitor of Cyclophilin A (CypA) and a receptor antagonist of Lysophosphatidic acid 1 (LPA1). HL001 induces cell cycle arrest and apoptosis of tumor cells by p53. HL001 stabilizes p53 by down-regulating G3BP1, inducing reactive oxygen species and DNA damage. HL001 disrupts the interaction between MDM2 and p53-72R in a CypA dependent manner. HL001 has antitumor activity. HL001 can also be used to study pulmonary fibrosis.
    HL001
  • HY-12579
    RO 2468
    		Inhibitor
    RO 2468 is a potent, orally active and selective p53-MDM2 inhibitor. RO 2468 has anti-proliferative active. RO 2468 suppresses c growth in SJSA1 osteosarcoma models without obvious toxicity.
    RO 2468
  • HY-175000
    L14-8
    		Agonist
    L14-8 is a potent ferroptosis inducer. L14-8 promotes PLK1 degradation via ubiquitination, increasing TP53 phosphorylation to enhance SAT1 transcription, thereby triggering ferroptosis and cancer cell death. L14-8 can be used for the study of advanced prostate cancer.
    L14-8
  • HY-149250
    MDMX/MDM2-IN-2
    		Inhibitor
    MDMX/MDM2-IN-2 is a potent p53-MDM2/MDMX dual inhibitors with Kis of 0.23 μM and 2.45 μM for MDM2 and MDMX, respectively. MDMX/MDM2-IN-2 inhibits the binding of p53 and MDM2 proteins. MDMX/MDM2-IN-2 restores the function of p53 and enables cell cycle arrest and apoptosis. MDMX/MDM2-IN-2 inhibits cell migration and invasion. MDMX/MDM2-IN-2 has antitumor activity.
    MDMX/MDM2-IN-2
  • HY-W708917
    Lumichrome-d8
    Lumichrome-d8 is the deuterium labeled Lumichrome (HY-115385). 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.
    Lumichrome-d<sub>8</sub>
  • HY-N0068R
    Solasodine (Standard)
    		MDM2 Inhibitor
    Solasodine (Standard) is the analytical standard of Solasodine. This product is intended for research and analytical applications. Solasodine (Purapuridine) is a steroidal alkaloid that occurs in plants of the Solanaceae family. Solasodine has neuroprotective, antifungal, hypotensive, anticancer, antiatherosclerotic, antiandrogenic and anti-inflammatory activities.
    Solasodine (Standard)
  • HY-128843
    PROTAC MDM2 Degrader-4
    		MDM2 Inhibitor
    PROTAC MDM2 Degrader-4 is a MDM2 degrader based on PROTAC technology. PROTAC MDM2 Degrader-4 composes of a potent MDM2 inhibitor, linker, and the MDM2 ligand for E3 ubiquitin ligase.
    PROTAC MDM2 Degrader-4
  • HY-174301
    USP7-IN-18
    		Activator
    USP7-IN-18 is a naphthalene derivative. USP7-IN-18 is a selective USP7 inhibitor (IC50 : 130.9 nM), with no or very weak inhibition of the other 8 DUBs including USP47. USP7-IN-18 specifically binds to the catalytic domain of USP7, blocking its deubiquitinase activity. USP7-IN-18 causes degradation of the oncogenic proteins MDM2 and DNMT1, and also degrades the novel target PCLAF. USP7-IN-18 activates the p53-p21 pathway. USP7-IN-18 exerts anti-tumor effects in colon cancer animal models and reshapes the tumor immune microenvironment. USP7-IN-18 achieves both direct cytotoxic and immune-synergistic anti-tumor actions.
    USP7-IN-18
  • HY-175332
    Apoptosis inducer 43
    		Inhibitor
    Apoptosis inducer 43 is an apoptosis inducer. Apoptosis inducer 43 can induce apoptosis, SubG0-G1 cell cycle arrest, secondary necrosis, and upregulate caspase-3, p53, and Bax/Bcl-2 expression in HCT116 cells. Apoptosis inducer 43 can inhibit tumor growth in a solid Ehrlich carcinoma (SEC) mouse model. Apoptosis inducer 43 can be used to study cancers such as colon cancer, leukemia, and non-small cell lung cancer.
    Apoptosis inducer 43
  • HY-168606A
    p53-MDM2-IN-7 hydrochloride
    		Inhibitor
    p53-MDM2-IN-7 (compound 6d) (hydrochloride) is a p53-MDM2 inhibitor. p53-MDM2-IN-7 has an IC50 value of 8.13 μM against A549 cells. p53-MDM2-IN-7 can be used in anti-cancer research.
    p53-MDM2-IN-7 hydrochloride
  • HY-P5343
    p53 CBS
    p53 CBS (p53 Consensus binding sequence) is a biological active peptide. (p53 consensus DNA binding site)
    p53 CBS
  • HY-145907
    p53-HDM2-IN-1
    		Inhibitor
    p53-HDM2-IN-1 is a potent inhibitor of p53-HDM2 protein-protein interaction, with an IC50 of 0.103 μM. p53-HDM2-IN-1 can be used for the research of cancer.
    p53-HDM2-IN-1
  • HY-133760
    MI-888
    		Inhibitor
    MI-888 is an orally active MDM2 inhibitor with a Ki of 0.44 nM. MI-888 can inhibit the MDM2-p53 interaction. MI-888 has favorable pharmacokinetic properties and anti-tumor activity.
    MI-888
  • HY-W750535
    Triglycidyl Isocyanurate-d15
    Triglycidyl Isocyanurate-d15 is the deuterium labeled Triglycidyl isocyanurate (HY-W011434). 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-d<sub>15</sub>
  • HY-123950
    MMRi64
    		Inhibitor 98.0%
    MMRi64 disrupts Mdm2-MdmX interactions. MMRi64 downregulates Mdm2 and MdmX in leukemia cells. MMRi64 induces p53 accumulation, and induces the apoptotic arm of the p53 pathway in leukemia/lymphoma cells. MMRi64 can be used for cancer research.
    MMRi64
  • HY-170595
    PROTAC LZK-IN-1
    		Inhibitor
    PROTAC LZK-IN-1 (Compound 21A) is a PROTAC that targets the degradation of LZK (Leucine Zipper Kinase, encoded by MAP3K13). PROTAC LZK-IN-1 (10 μM) promotes the degradation of LZK and inhibits the expression of p53 and c-MYC, leading to reduced viability of global head and neck squamous cell carcinoma (HNSCC) cell lines. PROTAC LZK-IN-1 can be used in cancer research. PROTAC LZK-IN-1 consists of an E3 ligase ligand (blue part, HY-112078), a target protein ligand (red part, HY-170596), and a linker (black part, HY-W019543)[1].
    PROTAC LZK-IN-1
  • HY-175034
    Topoisomerase I/II-IN-1
    		p53 Activator
    Topoisomerase I/II-IN-1 is a dual inhibitor of topoisomerase I/II. Topoisomerase I/II-IN-1 induces G2/M arrest and apoptosis in cancer cells by upregulating p53, p21, and Bax mRNA levels, caspase-3 protein levels, and the Bax/Bcl-2 ratio, while downregulating Bcl-2. Topoisomerase I/II-IN-1 is useful in the study of various cancers, including melanoma, renal cancer, colorectal cancer, and breast cancer.
    Topoisomerase I/II-IN-1
  • HY-178942
    EGFR/VEGFR2-IN-9
    		Activator
    EGFR/VEGFR2-IN-9 (Compound 9b) is an inhibitor of VEGFR-2 (IC50 = 1.325 μM) and EGFR (IC50 = 1.891 μM). EGFR/VEGFR2-IN-9 significantly inhibits the proliferation of multiple cancer cell lines, particularly leukemia cells. EGFR/VEGFR2-IN-9 upregulates the expression levels of Bax, caspase-3, and p53, while downregulating the expression of Bcl-2. EGFR/VEGFR2-IN-9 induces apoptosis and arrests the cell cycle in the G1 phase. EGFR/VEGFR2-IN-9 can be used to investigate anti-tumor angiogenesis and multi-drug resistant cancers.
    EGFR/VEGFR2-IN-9
  • HY-168636
    p53 Activator 13
    		Activator
    p53 Activator 13 (compound 11) is a 6mA methyltransferase CamA inhibitor and a p53 activator. p53 Activator 13 intercalates into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA and elicits DNA damage response via p53 activation. p53 Activator 13 can be utilized in cancer research.
    p53 Activator 13
  • HY-N6771R
    Cyclopiazonic acid (Standard)
    		Inducer
    Ancitabine (hydrochloride) (Standard) is the analytical standard of Ancitabine (hydrochloride). This product is intended for research and analytical applications. 0
    Cyclopiazonic acid (Standard)
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.