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-179409
    MC3817
    		Activator
    MC3817 is a selective DNMT1 inhibitor. MC3817 inhibits DNMT1 and DNMT3A/3L with IC50s of 0.044 μM and > 10μM, respectively. MC3817 inhibits P53-dependent cancer cell proliferation, induces apoptosis and DNA damage MC3817 elevates cleaved Caspase 3, P53, and γH2AX. MC3817 can be used in non-small cell lung cancer, colon cancer, cervical cancer, triple-negative breast cancer and histiocytic lymphoma research.
    MC3817
  • HY-W004702S
    Methyl methanesulfonate-d3
    		p53 Activator
    Methyl methanesulfonate-d3 is the deuterium labeled Methyl methanesulfonate (HY-W004702). Methyl methanesulfonate is an alkylating agent which transfers methyl groups, and induces DNA damage. Methyl methanesulfonate is a biochemical reagent that can be used as a biological material or organic compound for life science related research.
    Methyl methanesulfonate-d<sub>3</sub>
  • HY-P3508
    PNC-27
    		99.01%
    PNC-27, a chimeric p53-penetratin peptide binds to HDM-2 in a p53 peptide-like structure, induces selective membrane-pore formation and leads to cancer cell lysis. PNC-27 is an anticancer peptide. PNC-27 can be used in acute myeloid leukemia research.
    PNC-27
  • HY-W414644
    Fluacrypyrim
    		Inhibitor
    Fluacrypyrim, a Miticide, is a STAT3 inhibitor. Fluacrypyrim significantly increases the protein tyrosine phosphatases(PTPs) activity. Fluacrypyrim inhibits the growth of leukemia cells by a predominant G1 arrest with significant decrease of the protein and mRNA levels of cyclin D1. Fluacrypyrim selectively inhibits STAT3 signaling, inducing growth arrest and apoptosis in STAT3-dependent cancer cells. Fluacrypyrim mitigates IR-induced hematopoietic system injury mainly by preventing apoptosis in the HSCs. Fluacrypyrim demonstrates significant analgesic and anti-inflammatory effects by inhibiting uterine smooth muscle contraction and inflammatory responses.
    Fluacrypyrim
  • HY-156183
    Antiproliferative agent-37
    		Activator 98.29%
    Antiproliferative agent-37 (compound 10J) shows anti-proliferative effect by arresting the cells at the G2/M phase of the cell cycle.
    Antiproliferative agent-37
  • HY-116794
    SF5
    		Inhibitor 99.83%
    SF5 (2,2-Diphenylethyl isothiocyanate) is a sulforaphane analog. SF5 inhibits apoptosis by the JNK-p53-caspase pathway. SF5 can be used as a new renal protective agent for drug-resistant acute renal disease.
    SF5
  • HY-171499
    Cenersen
    		Inhibitor
    Cenersen (EL625) is an oligonucleotide targeting TP53. Cenersen can eliminate the activity of TP53 gain-of-function mutants and increase the sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. Cenersen can be used for the study of chronic lymphocytic leukemia (CLL).
    Cenersen
  • HY-17412S1
    Minocycline-d6 sulfate
    		p53 Activator
    Minocycline-d6 sulfate is deuterated labeled Minocycline (HY-17412A). Minocycline is an orally active, potent and BBB-penetrated semi-synthetic tetracycline antibiotic. Minocycline is a hypoxia-inducible factor (HIF)-1α inhibitor. Minocycline shows anti-cancer, anti-inflammatory, and glutamate antagonist effects. Minocycline reduces glutamate neurotransmission and shows neuroprotective properties and antidepressant effects. Minocycline inhibits bacterial protein synthesis through binding with the 30S subunit of the bacterial ribosome, resulting in a bacteriostatic effect.
    Minocycline-d<sub>6</sub> sulfate
  • HY-70027
    p53 and MDM2 proteins-interaction-inhibitor (chiral)
    		MDM2 Inhibitor 98.13%
    p53 and MDM2 proteins-interaction-inhibitor (chiral) (Compound 32) is an inhibitor of the interaction between p53 and MDM2 proteins.
    p53 and MDM2 proteins-interaction-inhibitor (chiral)
  • HY-12287
    YH239-EE
    		MDM2 Inhibitor 98.28%
    YH239-EE, ethyl ester of the free carboxylic acid compound YH239, is a potent p53-MDM2 antagonizing and apoptosis-inducing agent.
    YH239-EE
  • HY-110315A
    Ischemin
    		Inhibitor 99.80%
    Ischemin is a CBP bromodomain inhibitor that inhibits p53 interaction with CBP and transcriptional activity in cells. Ischemin inhibits p53-induced p21 activation with an IC50 value of 5 µM. Ischemin also prevents apoptosis in ischemic cardiomyocytes. Ischemin can be used in the study of cardiovascular diseases (such as myocardial ischemia).
    Ischemin
  • HY-B0294R
    Flubendazole (Standard)
    		Activator
    Flubendazole (Standard) is the analytical standard of Flubendazole. This product is intended for research and analytical applications. Flubendazole is an anthelmintic drug based on altering microtubule structure, inhibition of tubulin polymerization and disruption of microtubule function. Flubendazole induces apoptosis in human colorectal cancer (CRC) by blocking the STAT3 signaling axis and activation of autophagy. Flubendazole induces P53 expression and reduced Cyclin B1 and p-cdc2 expression. Flubendazole is an antitumor agent. Flubendazole can be used for worm and intestinal parasites.
    Flubendazole (Standard)
  • HY-B0774R
    Seratrodast (Standard)
    		Inhibitor
    Seratrodast (Standard) is the analytical standard of Seratrodast. This product is intended for research and analytical applications. Seratrodast (AA 2414), an orally active antiasthmatic agent, is a thromboxane A2 receptor (TP) antagonist and ferroptosis inhibitor. Seratrodast reduces lipid ROS production, modulates the systemic xc-/GSH/GPX4 axis, and inhibits JNK phosphorylation and p53 expression. Seratrodast exhibits anti-asthmatic and anti-epileptic activity.
    Seratrodast (Standard)
  • HY-W654013
    Minocycline-d7
    		p53 Activator
    Minocycline-d7 is deuterium labeled Minocycline. Minocycline is an orally active, potent and BBB-penetrated semi-synthetic tetracycline antibiotic. Minocycline is a hypoxia-inducible factor (HIF)-1α inhibitor. Minocycline shows anti-cancer, anti-inflammatory, and glutamate antagonist effects. Minocycline reduces glutamate neurotransmission and shows neuroprotective properties and antidepressant effects. Minocycline inhibits bacterial protein synthesis through binding with the 30S subunit of the bacterial ribosome, resulting in a bacteriostatic effect.
    Minocycline-d<sub>7</sub>
  • HY-16055
    Silatecan
    Silatecan (AR-67) is a blood-brain barrier-permeable derivative of Camptothecin (HY-16560), DNA topoisomerase I inhibitor, an anticancer agent, and a radiosensitizer. Silatecan potently radiosensitizes wild-type p53 gliomas. Silatecan can be used in research related to glioma, leukemia, non-small cell lung cancer, colon cancer, ovarian cancer, renal cancer, prostate cancer, breast cancer, cervical cancer, gastric cancer, nasopharyngeal cancer, and uterine cancer.
    Silatecan
  • 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-120667
    DS-5272
    		Inhibitor
    DS-5272 is an orally acitve inhibitor for p53-MDM2 with an IC50 of 20 nM. DS-5272 inhibits the proliferation of SJSA-1 (wildtype p53, IC50=0.17 μM) and DLD-1 (mutant p53). DS-5272 arrest the cell cycle, and induces apoptosis in SJSA-1. DS-5272 exhibits antitumor efficacy in mice.
    DS-5272
  • HY-139846
    MK-4688
    		Inhibitor
    MK-4688 is an efficient inhibitor of the HDM2-p53 protein-protein interaction.
    MK-4688
  • HY-112816A
    MA242 free base
    		MDM2 Inhibitor
    MA242 free base is a specific dual inhibitor of MDM2 and NFAT1. MA242 free base directly binds both MDM2 and NFAT1 with high affinity, induces their protein degradation, and inhibits NFAT1-mediated transcription of MDM2. MA242 free base induces apoptosis in pancreatic cancer cell lines regardless of p53 status.
    MA242 free base
  • HY-174458
    MD-4251
    		Degrader
    MD-4251 is an orally active MDM2 PROTAC degrader. MD-4251 potently degrades MDM2 in RS4;11 cells (DC50: 0.2 nM) and actives p53. MD-4251 shows strong antiproliferative activity against acute leukemia cells (wild-type p53) with minimal efficacy in mutant type. MD-4251 induces complete tumor regression in RS4;11 xenograft mice model. Pink: MDM2 ligand (HY-130684); Blue: CRBN ligase ligand (HY-W883326); Black: linker
    MD-4251
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.