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-150620
    BI-0282
    		Inhibitor
    BI-0282 (Compound 1) is a potent MDM2-p53 interaction inhibitor.
    BI-0282
  • HY-181616
    p53-Y220C/PLK1 modulator-1
    		Modulator
    p53-Y220C/PLK1 modulator-1 (compound15) is a dual modulator targeting p53-Y220C and PLK1. p53-Y220C/PLK1 modulator-1 can be used in the cancer.
    p53-Y220C/PLK1 modulator-1
  • 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
  • HY-175538
    USP10-IN-4
    		Inhibitor
    USP10-IN-4 is a potent ubiquitin-specific protease 10 (USP10) inhibitor with an IC50 of 10.87 μM and a Kd of 365 nM. USP10-IN-4 effectively inhibits USP10-mediated proteasomal degradation of downstream proteins YAP and p53, leading to the subsequent downregulation of CDK4 in the p53 signaling pathway. USP10-IN-4 promotes apoptosis in HCC cells and inhibits the onset and progression of liver cancer. USP10-IN-4 can used for the study of hepatocellular carcinoma (HCC).
    USP10-IN-4
  • HY-170591
    p53 Activator 14
    		p53 Activator
    p53 Activator 14 (Compound 7A) is a derivative of Neratinib (HY-32721), that induces DNA damage, activates p53, and inhibits the proliferation of multi cancer cells (IC50=7.21 μM for HCT116 cell). p53 Activator 14 inhibits the adhesion, migration and invasion of HCT116, arrests the cell cycle, and induces apoptosis. p53 Activator 14 inhibits angiogenesis and exhibits antitumor efficacy in chick chorioallantoic membrane (CAM) model.
    p53 Activator 14
  • HY-125660
    Leucettamol A
    		Activator
    Leucettamol A is an inhibitor of Ubc13 (ubiquitin E2 enzyme)-Uev1A interaction, with an IC50 of 50 μg/mL. Leucettamol A can potentially activate the expression of cancer suppressor p53 and is a precursor of anticancer agents. Leucettamol A can be isolated from a marine sponge, Leucetta aff. Microrhaphis.
    Leucettamol A
  • HY-108919
    CG-1521
    		p53 Activator
    CG-1521 is a histone deacetylase (HDAC) inhibitor that stabilizes Ac-Lys373 P53, increases P21 levels and HDAC2 degradation. CG-1521 can inhibit proliferation, induce cell cycle arrest and apoptosis. CG-1521 promotes Bax translocation to the mitochondria and cleavage. CG-1521 downregulates KIF4, Aurora B and Nek2 protein expression and DNA synthesis. CG-1521 can be used for the research of prostate cancer and inflammatory breast cancer.
    CG-1521
  • HY-118912
    BMH-9
    		Activator
    BMH-9 (Compound Z54) is a modulator for nuclear receptor subfamily 2, group F, member 6 (NR2F6) (also known as nuclear orphan receptor Ear2). BMH-9 is an activator for p53 signaling pathway through interaction with DNA. BMH-9 inhibits proliferation of human cancer cells, exhibits antitumor efficacy in NOD-SCID mouse models.
    BMH-9
  • HY-179506
    p53 Activator 16
    		Activator
    P53 Activator 16 (Compound JC16) is a p53 activator. P53 Activator 16 exhibits selective cytotoxicity and pro-apoptotic (apoptosis) activity towards p53-Y220C mutant cancer cells, while having little effect on wild-type or P53-deficient cells. P53 Activator 16 induces the conformational transition of cell p53-Y220C from the mutant form to the wild-type form, accompanied by the transcriptional activation of p53 target genes, without increasing the overall level of p53 protein. P53 Activator 16 can be used for the study of p53 mutant cancers.
    p53 Activator 16
  • HY-17493A
    MI-773 TFA
    		Inhibitor 98.91%
    MI-773 TFA is an orally active, selective MDM2-p53 interaction inhibitor with a Ki of 0.88 nM for MDM2. MI-773 TFA blocks the MDM2-TP53 interaction. MI-773 TFA potently activates p53. MI-773 TFA induces Apoptosis. MI-773 TFA causes tumor regression in xenograft models of adenoid cystic carcinoma. MI-773 TFA exhibits anticancer effects in neuroblastoma. MI-773 TFA can be used for the research of adenoid cystic carcinoma.
    MI-773 TFA
  • HY-175019
    VEGFR-2-IN-70
    		Agonist
    VEGFR-2-IN-70 is a potent VEGFR-2 inhibitor with an IC50 of 18.04 nM. VEGFR-2-IN-70 exhibits cytotoxicity against A549 and MCF-7 cancer cells with IC50 values of 0.43 μM and 3.8 μM, respectively. VEGFR-2-IN-70 induces G1 cell cycle arrest and apoptosis in lung cancer cells. VEGFR-2-IN-70 is useful in cancer research.
    VEGFR-2-IN-70
  • HY-144104
    NSC90616
    		Activator
    NSC90616 is a mutant p53 rescue compound.
    NSC90616
  • HY-W287494
    Antitumor agent-202
    		Modulator
    Antitumor agent-202 is a stabilizer of the p53 Y220C mutant. It exhibits a selective inhibitory effect on the proliferation of tumor cells carrying the p53 Y220C mutation and can be applied to the research of cancers associated with the p53 Y220C mutation.
    Antitumor agent-202
  • HY-16270
    Kevetrin
    		Activator
    Kevetrin (3-Cyanopropyl carbamimidothioate; 4-Isothioureidobutyronitrile) is an apoptosis inducer that exhibits p53-dependent and p53-independent antitumor activity. In TP53 wild-type models, Kevetrin activates and stabilizes the p53 protein by altering the processing of MDM2, thereby inducing cell cycle arrest and apoptosis. Kevetrin shows higher sensitivity in mutant models. Kevetrin is applicable for the research of various cancers including acute myeloid leukemia and breast cancer.
    Kevetrin
  • HY-179155
    PI3K/mTOR-IN-19
    		Activator
    PI3K/mTOR-IN-19 is an orally active, potent, selective PI3K (IC50 = 4.23 nM) and mTOR (IC50 = 2.3 nM) inhibitor. PI3K/mTOR-IN-19 significantly inhibits Eca109 cell viability and induces apoptosis. PI3K/mTOR-IN-19 causes G0/G1 cell cycle arrest, decreased mitochondrial membrane potential, and demonstrates marked telomerase inhibitory activity. PI3K/mTOR-IN-19 modulates the expression of key apoptotic regulators (Bcl-2, Bax, and p53) and downregulates the PI3K/Akt/mTOR signaling pathway. PI3K/mTOR-IN-19 can be used for the study of esophageal cancer.
    PI3K/mTOR-IN-19
  • 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-179129
    AKT-100
    		Activator
    AKT-100 is a p53 reactivation agent. AKT-100 significantly inhibits the proliferation of various ovarian and endometrial cancer cells at low concentrations. AKT-100 can upregulate cell cycle regulatory genes (such as p21, GADD45) and pro apoptotic genes (such as NOXA, DR5), and inhibit DNA repair pathways. AKT-100 is commonly used in cancer research.
    AKT-100
  • 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-183330
    Topo I/II-IN-3
    		Activator
    Topo I/II-IN-3 is a dual inhibitor of topoisomerase I/II (topoisomerase I/II), with an IC50 of 8.99 μM against Topo I and an IC50 of 26.92 μM against Topo II. Topo I/II-IN-3 induces DNA damage, elevates intracellular ROS levels, activates the mitochondrial apoptosis pathway, and exerts cytotoxicity against cancer cells. Topo I/II-IN-3 upregulates the expression of γ-H2AX, p53, activated caspase-9, Bax and activated caspase-3, while downregulating the expression of Bcl-2. Topo I/II-IN-3 can be used in research related to breast cancer, liver cancer and gastric cancer.
    Topo I/II-IN-3
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.