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-18331
    MI-219
    		MDM2 Inhibitor
    MI-219 is an antagonist for MDM2 with a Ki of 13.3 μM. MI-219 inhibits the MDM2-p53 interaction, inhibits thus the proliferation of FSCCL cells, with an IC50 of 2.5 μM.
    MI-219
  • HY-W281364S
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine-13C
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine-13C is the 13C-labeled 2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine (HY-W281364). 2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine is a mutagenic compound.
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine-<sup>13</sup>C
  • HY-146389
    Anticancer agent 50
    		Inducer
    Anticancer agent 50 (compound 6) is a potent ABCB1 efflux pump modulator. Anticancer agent 50 shows cytotoxic effects and antiproliferative effects. Anticancer agent 50 decreases the expression of cyclin D1 and induces p53 expression. Anticancer agent 50 has the potential for the research of T-lymphoma.
    Anticancer agent 50
  • HY-B2054S
    Tebufenozide-d9
    		p53 Activator
    Tebufenozide-d9 is the deuterium labeled Tebufenozide (HY-B2054). Tebufenozide is a nonsteroidal ecdysone agonist used to control pest. Tebufenozide has cytotoxic and induces apoptosis in HeLa and insect Tn5B1-4 cells.
    Tebufenozide-d<sub>9</sub>
  • HY-151170
    MDM2/4-p53-IN-2
    		Inhibitor
    MDM2/4-p53-IN-2 (2q) is a potent dual MDM2/ MDM4 inhibitor and p53 activator with the IC50 values of 70.7 nM for MDM2- p53 and 81.4 nM for MDM4-p53 complexes. MDM2/4-p53-IN-2 regulates the cell cycle, induces cell apoptosis and has anticancer activity.
    MDM2/4-p53-IN-2
  • HY-116052
    p53-MDM2-IN-2
    		Inhibitor
    p53-MDM2-IN-2 (Compound 5q) is an orally active p53-MDM2 inhibitor with a Ki value of 0.25 μM. p53-MDM2-IN-2 exerts antitumor activity by inhibiting NF-κB pathway.
    p53-MDM2-IN-2
  • 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-108433
    CPT2
    		Activator
    CPT2 (Carnitine palmitoyltransferase 2), an enzyme that participates in fatty acid oxidation, also is a colorectal cancer (CRC) prognostic biomarker. CPT2 overexpression can activate p-p53 to increase p53 expression, thereby inhibiting tumor proliferation and promoting apoptosis. CPT2 deficiency results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. Downregulation of CPT2 is also highly correlated with the progression of various cancers and has potential for cancer research.
    CPT2
  • 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-169240
    MX69-102
    		Activator
    MX69-102 (compound MX69-102) is an MDM-2/p53 inhibitor, inducing MDM2 degradation, resulting in p53 activation and cancer cell apoptosis. MX69-102 shows effective inhibition on xenografted human MDM2-overexpressing ALL in SCID mice..
    MX69-102
  • HY-133754
    MI-1063
    		MDM2 Inhibitor
    MI-1063 is an inhibitor for DMD-2, that blocks the MDM2-p53 interaction, and activates the tumor suppressor function of p53. MI-1063 inhibits the growth of cancer cell RS4-11 and MV4-11 with IC50 of 179 nM and 93 nM. MI-1063 can be used as target protein ligand in synthesis of PROTAC degrader MD-265 (HY-169327).
    MI-1063
  • HY-162450
    Antitumor agent-150
    		MDM2 Inhibitor
    Antitumor agent-150 (V10), an anti-breast cancer agent, is a PROTAC-based MDM2 protein degrader (Red: Ganoderic acid A; Black: 4O-PEG linker; Blue: VHL ligand).
    Antitumor agent-150
  • HY-162247
    MDM2-IN-26
    		Inhibitor
    MDM2-IN-26 (compound A3) is an MDM2 inhibitor that can activate the tumor suppressor function of p53 by blocking the interaction between MDM2 and p53 (MDM2 is the main negative regulator of p53). MDM2-IN-26 can be used for cancer research.
    MDM2-IN-26
  • HY-151172
    MDM2-p53-IN-15
    		Inhibitor
    MDM2-p53-IN-15 is a MDM2-p53 inhibitor with an IC50 value of 26.1 nM. MDM2-p53-IN-15 inhibits the proliferation of various cancer cells and induces cell apoptosis. MDM2-p53-IN-15 can be used for the research of cancer.
    MDM2-p53-IN-15
  • HY-N2037AS1
    Higenamine-d4-1 hydrochloride
    		Activator
    Higenamine-d4-1 (Norcoclaurine-d4-1) hydrochloride is deuterium labeled Higenamine (hydrochloride). Higenamine hydrochloride is a selective LSD1 inhibitor (IC50=1.47 μM) that can be isolated from aconite. Higenamine hydrochloride has anti-inflammatory and antibacterial activity. Higenamine (Norcoclaurine) can attenuate IL-1β-induced Apoptosis through ROS-mediated PI3K/Akt signaling pathway. Higenamine hydrochloride protects brain cells from oxygen deprivation. Higenamine can promote bone formation in osteoporosis through the SMAD2/3 pathway. Higenamine hydrochloride can be used to study cancer, inflammation, cardiorenal syndrome and other diseases.
    Higenamine-d<sub>4</sub>-1 hydrochloride
  • HY-W751400
    Solasodine hydrochloride
    		Inhibitor
    Solasodine (Purapuridine) hydrochloride is a steroidal alkaloid that occurs in plants of the Solanaceae family. Solasodine hydrochloride induces apoptosis by inhibiting the p53-MDM2 complex, p21Waf1/Cip1, and Bcl-2 proteins. Solasodine hydrochloride has neuroprotective, antifungal, hypotensive, anticancer, antiatherosclerotic, antiandrogenic and anti-inflammatory activities.
    Solasodine hydrochloride
  • HY-N7264R
    7α-Hydroxycholesterol (Standard)
    7α-Hydroxycholesterol is a cholesterol oxide and can serve as a biomarker for oxidative stress and lipid peroxidation. 7α-Hydroxycholesterol has cytotoxic and pro-inflammatory activities. 7α-Hydroxycholesterol can also inhibit sterol synthesis and reduce the activity of HMG-CoA reductase. 7α-Hydroxycholesterol can be used in the research of diseases such as diabetes and atherosclerosis.
    7α-Hydroxycholesterol (Standard)
  • HY-118542
    Nutlin 1
    		Antagonist
    Nutlin 1, an antagonist of MDM2, activates a major cellular function of the p53 pathway, with an IC50 value of 0.26 μM.
    Nutlin 1
  • HY-167635
    Decarbamoylmitomycin C
    		p53 Activator
    Decarbamoylmitomycin C, an analog of Mitomycin C (MC), is an DNA-alkylating agent. Decarbamoylmitomycin C (DMC) activates p53-independent ataxia telangiectasia and rad3 related protein (ATR) chromatin eviction.
    Decarbamoylmitomycin C
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.