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-N7271R
    Solanidine (Standard)
    		Activator
    Solanidine (Standard) is the analytical standard of Solanidine. This product is intended for research and analytical applications. Solanidine is an orally active cholestane alkaloid. Solanidine can be isolated from potato. Solanidine decreases RAD51 and increases γH2AX and p53. Solanidine has anti-tumor effects on LLC tumors and lung cancer. Solanidine promotes breast cancer cell proliferation. Solanidine reduces neovascularization. Solanidine causes abortion in some pregnant mice.
    Solanidine (Standard)
  • HY-139458
    MDM2-IN-21
    		MDM2 Inhibitor
    MDM2-IN-21 is a potent MDM2 inhibitor. MDM2-IN-21 can be used for the research of cancer.
    MDM2-IN-21
  • HY-158151
    p53 Activator 12
    		Activator
    p53 Activator 12 (compound 510B) is a potent p53 activator. p53 Activator 12 binds to mutant p53 and restores the ability of the p53 mutant to bind DNA.
    p53 Activator 12
  • HY-161874
    RPS6-IN-1
    		Inducer
    RPS6-IN-1 (Compound 22o) inhibits cell metastasis, induces cell apoptosis (increases the expression of Bax, p53, cleaved-caspase 3, and cleaved-PARP). RPS6-IN-1 decreases mitochondrial membrane potential. RPS6-IN-1 activates autophagy through the PI3K-Akt-mTOR signaling pathway, damages intracellular mitochondria and lysosomes, and cause ER stress. RPS6-IN-1 inhibits RPS6 phosphorylation. RPS6-IN-1 is an anticancer agent with low systemic toxicity.
    RPS6-IN-1
  • HY-12296S
    Navtemadlin-d7
    		MDM2 Inhibitor
    Navtemadlin-d7 is the deuterium labeled Navtemadlin. Navtemadlin (AMG 232) is a potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC50 of 0.6 nM. Navtemadlin binds to MDM2 with a Kd of 0.045 nM.
    Navtemadlin-d<sub>7</sub>
  • HY-123544
    RDR03871
    		MDM2 Inhibitor
    RDR03871 (compound 2) is a potent dual MDM2/MDM4 inhibitor with IC50 values of 35.4 nM and 10.4 nM for MDM2-p53 and MDM4-p53, respectively.
    RDR03871
  • HY-16634
    MI-888 TFA
    		Inhibitor
    MI-888 (TFA) is an orally active MDM2-p53 interaction inhibitor with a Ki of 0.44 nM. MI-888 (TFA) can achieve rapid, complete, and sustained tumor regression in a xenograft mouse model of cancer.
    MI-888 TFA
  • HY-160449
    p53 Activator 10
    		Activator
    p53 Activator 10 (Example C-2) is a compound that targets the y220c mutant of p53. p53 Activator 10 activation is involved in the downstream effects of tumor suppression.
    p53 Activator 10
  • HY-149988
    UNP-6457
    		Inhibitor
    UNP-6457 is a potent active MDM2-p53 interaction inhibitor with an IC50 values of 8.9 nM.
    UNP-6457
  • HY-N2037AS
    Higenamine-d4 hydrochloride
    		Activator
    Higenamine-d4 (Norcoclaurine-d4; Demethyl-Coclaurine-d4) hydrochloride is deuterium-labeled Higenamine (hydrochloride) (HY-N2037A).
    Higenamine-d<sub>4</sub> hydrochloride
  • HY-151171
    MDM2/4-p53-IN-3
    		Inhibitor
    MDM2/4-p53-IN-3 is a MDM2/4-p53 protein-protein interactions (PPIs) inhibitor (IC50s: 18.5 nM for MDM2-p53, 14.8 nM for MDM4-p53). MDM2/4-p53-IN-3 can be used in the research of cancers, such as colon cancer.
    MDM2/4-p53-IN-3
  • HY-149024
    VEGFR-2-IN-23
    		p53 Activator
    VEGFR-2-IN-23 (compound 11b) is a potent and selective VEGFR-2 inhibitor with an IC50 value of 0.34 nM. VEGFR-2-IN-23 shows antitumor activity. VEGFR-2-IN-23 induces apoptosis and cell cycle arrest at G1 phase.
    VEGFR-2-IN-23
  • HY-B0860R
    Diuron (Standard)
    		Activator
    Diuron (Standard) is the analytical standard of Diuron (HY-B0860). This product is intended for research and analytical applications. Diuron is an orally active phenylurea herbicide. Diuron inhibits photosynthesis in plants by blocking the formation of ATP and NADH. Diuron increases the production of ROS. Diuron increases expression of p53 in certain cell lines. Diuron has herbicidal activity against annual and perennial broadleaf weeds and grass weeds. Diuron promotes DMBA/BBN-induced bladder cancer. Diuron can be used in breast cancer research.
    Diuron (Standard)
  • HY-171272
    PRDX1-IN-3
    		Activator
    PRDX1-IN-3 (compound 19-048) is a PRDX1 covalent inhibitor with anti-colorectal cancer activity. PRDX1-IN-3 can effectively inhibit the proliferation of colorectal cancer cells, and its antitumor effect on nude mice with colorectal cancer carrying PRDX1 gene knockout is significantly reduced. PRDX1-IN-3 also upregulates the downstream genes of the p53 signaling pathway to exert an anticancer effect.
    PRDX1-IN-3
  • HY-163275
    MDM2-IN-24
    		Inhibitor
    MDM2-IN-24 (compound A3f) exhibits MDM2-inhibiting and MDMX-activating properties in triple-negative breast cancer (TNBC) cells, with apoptotic and anti-proliferative activities.
    MDM2-IN-24
  • HY-176457
    ZS3-046
    		Activator
    ZS3-046 is a TAF1 PROTAC degrader. ZS3-046 promotes the ubiquitination and degradation of TAF1. ZS3-046 activates p53 and induces apoptosis in acute myeloid leukemia (AML) cells. ZS3-046 has antitumor activity in an AML tumor xenograft mouse model. (Target protein ligand (HY-176467); CRBN ligase (HY-41547); Linker (HY-176469); CRBN ligase + Linker (HY-176470)).
    ZS3-046
  • HY-108640
    HLI373
    		MDM2 Inhibitor
    HLI373 is an efficacious Hdm2 inhibitor. HLI373 inhibits the ubiquitin ligase activity of Hdm2. HLI373 is effective in inducing apoptosis of several tumor cells that are sensitive to DNA-damaging agents. Antimalarial activity.
    HLI373
  • HY-150620
    BI-0282
    		Inhibitor
    BI-0282 (Compound 1) is a potent MDM2-p53 interaction inhibitor.
    BI-0282
  • HY-158210
    Wnt/β-catenin-IN-3
    		Inducer
    Wnt/β-catenin-IN-3 (compound 17) is a Wnt/β-catenin inhibitor with low micromolarGI50s against various cancer cells. Wnt/β-catenin-IN-3triggers G2/M cell cycle arrest though activation of p53-p21 pathway as well as intrinsic and extrinsic apoptotic death of colon cancer cells.
    Wnt/β-catenin-IN-3
  • HY-N15314
    Syringolin A
    		p53 Activator
    Syringolin A is a plant elicitor that can be produced by the plant pathogen Pseudomonas syringae pv. syringae. Syringolin A exhibits anti-proliferative activity against a variety of cancer cells (IC50 for SK-N-SH, LAN-1, SKOV3 is 20-25 µM), induces apoptosis in SK-N-SH through upregulation of p53 expression and downregulation of Akt/PKB proteins.
    Syringolin A
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.