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-N7271
    Solanidine
    		Activator 99.90%
    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
  • HY-120086
    RO-5963
    		MDM2 Inhibitor 99.97%
    RO-5963 is a dual p53-MDM2 and p53-MDMX inhibitor with IC50s of ~17 nM and ~24 nM, respectively.
    RO-5963
  • HY-15510B
    Tenovin-6 Hydrochloride
    		p53 Activator 98.88%
    Tenovin-6 Hydrochloride, an analog of Tenovin-1 (HY-13423), is an activator of p53 transcriptional activity. Tenovin-6 Hydrochloride inhibits the protein deacetylase activities of purified human SIRT1, SIRT2, and SIRT3 with IC50s of 21 μM, 10 μM, and 67 μM, respectively. Tenovin-6 Hydrochloride also inhibits dihydroorotate dehydrogenase (DHODH).
    Tenovin-6 Hydrochloride
  • HY-160922
    BAY 249716
    		99.03%
    BAY 249716 stabilizes all three p53 protein variants. BAY 249716 also has antitubercular activity (IC90: <0.10 μg/mL for Tuberculosis).
    BAY 249716
  • HY-120122
    PK7088
    		99.11%
    PK7088 is a pyrazole and a specific peptide. PK7088 supports the reactivation of mutant p53 by converting it to a form exhibiting wild-type properties. PK7088 exhibit anticancer activity in cancer research.
    PK7088
  • HY-138054
    Cjoc42
    		≥99.0%
    Cjoc42 is a compound capable of binding to gankyrin. Cjoc42 inhibits gankyrin activity in a dose-dependent manner. Cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin. Cjoc42 restores p53-dependent transcription and sensitivity to DNA damage.
    Cjoc42
  • HY-120149
    Inotodiol
    		Activator 98.29%
    Inotodiol activates p53 signaling pathway, inhibits MMP-2/9, and exhibits antitumor activity in cancer cell HeLa. Inotodiol inhibits the generation of ROS and exhibits antioxidant and neuroprotective effects. Inotodiol inhibits the activation of MAPK and NF-κB signaling pathway, and exhibits anti-inflammatory activity. Inotodiol inhibits TLR-4 mediated TNF-α production (IC50s in BMMC and BMDM is 0.7 μM and 3.0 μM), inhibits the degranulation in mast cell, exhibits anti-allergic activity. Inotodiol is orally active.
    Inotodiol
  • HY-143692
    SQDG
    		p53 Activator ≥99.0%
    SQDG inhibits topoisomerase I and P-selectin receptor, exhibits anti-inflammatory, antiviral and antitumor activities. SQDG is a glycolipid that possesses sugar moieties in their head groups. SQDG is a membrane lipid that can be used to investigate the effects of structural lipid in LNP formulations.
    SQDG
  • HY-17412R
    Minocycline hydrochloride (Standard)
    		p53 Activator
    Minocycline (hydrochloride) (Standard) is the analytical standard of Minocycline (hydrochloride). This product is intended for research and analytical applications. Minocycline hydrochloride is an orally active, potent and BBB-penetrated semi-synthetic tetracycline antibiotic. Minocycline hydrochloride is a hypoxia-inducible factor (HIF)-1α inhibitor. Minocycline hydrochloride shows anti-cancer, anti-inflammatory, and glutamate antagonist effects. Minocycline hydrochloride reduces glutamate neurotransmission and shows neuroprotective properties and antidepressant effects. Minocycline hydrochloride inhibits bacterial protein synthesis through binding with the 30S subunit of the bacterial ribosome, resulting in a bacteriostatic effect.
    Minocycline hydrochloride (Standard)
  • HY-10412
    CEP-1347
    		p53 Activator 98.50%
    CEP-1347 is an inhibitor of the JNK/SAPK pathway with neuroprotective effects. CEP-1347 blocks JNK1 activation induced by members of the mixed lineage kinase (MLK) family (MLK3, MLK2, MLK1, dual leucine zipper kinase, and leucine zipper kinase). As an inhibitor of MDM4, CEP-1347 can more effectively inhibit the growth of glioma cells expressing wild-type p53.
    CEP-1347
  • HY-100383
    BH3I-1
    		MDM2 Inhibitor ≥98.0%
    BH3I-1 is a Bcl-2 family antagonist, which inhibits the binding of the Bak BH3 peptide to Bcl-xL with a Ki of 2.4±0.2 μM in FP assay. BH3I-1 has a Kd of 5.3 μM against the p53/MDM2 pair.
    BH3I-1
  • HY-101266B
    Milademetan tosylate hydrate
    		MDM2 Inhibitor 98.89%
    Milademetan (DS-3032) tosylate hydrate is a specific and orally active MDM2 inhibitor for the research of acute myeloid leukemia (AML) or solid tumors. Milademetan (DS-3032) tosylate hydrate induces G1 cell cycle arrest, senescence and apoptosis.
    Milademetan tosylate hydrate
  • HY-149306
    MS78
    		99.38%
    MS78 is an acetylation targeting chimera (AceTAC) that acetylates the p53 tumor suppressor protein. MS78 recruits histone acetyltransferase p300/CBP to acetylate the p53Y220C mutant. MS78 upregulates TRAIL apoptotic genes and downregulates DNA damage response pathways. MS78 contains a CBP/p300 binder, a p53Y220C binder and a linker.
    MS78
  • HY-145759
    Mutant p53 modulator-1
    		Modulator 98.25%
    Mutant p53 modulator-1 is a mutant p53 modulator. Mutant p53 modulator-1 reduces the progression of cancers that contain a p53 mutation (extracted from patent WO2021231474A1, compound 231B).
    Mutant p53 modulator-1
  • HY-W013053
    Dibenz[a,h]anthracene
    		≥98.0%
    Dibenz[a,h]anthracene (DBA) is a polycyclic aromatic hydrocarbon (PAH) of considerable tumorigenicity. Dibenz[a,h]anthracene results in DNA adduct formation leading to the activation of a DNA damage response. Dibenz[a,h]anthracene induces cell cycle arrest and apoptosis via both Tp53-dependent and Tp53-independent mechanisms.
    Dibenz[a,h]anthracene
  • HY-128840
    PROTAC MDM2 Degrader-1
    		MDM2 Inhibitor 98.11%
    PROTAC MDM2 Degrader-1 (Compound 15a) is a MDM2 PROTAC degrader. The structures of both Linker ends of PROTAC MDM2 Degrader-1 are MDM2 ligands. PROTAC MDM2 Degrader-1 can not only block the binding of p53-MDM2, but also degrade the target MDM2 protein by utilizing the function of the E3 ligase of MDM2 itself, thus exerting an anti-tumor effect. (Pink: MDM2 ligand 2 (HY-128836); Black: Linker (HY-128844); Blue: E3 ligase Ligand 15 (HY-128836))
    PROTAC MDM2 Degrader-1
  • HY-145937
    PK9327
    		Modulator 98.50%
    PK9327 is a small-molecule stabilizer targeting cavity-creating p53 cancer mutations.
    PK9327
  • HY-148833
    MDM2-p53-IN-16
    		Inhibitor 99.11%
    MDM2-p53-IN-16 is a MDM2-p53 complex inhibitor with an IC50 value of 4.3 nM to dissociate human p53/MDM2 complex. MDM2-p53-IN-16 reactivates p53, and induces Glioblastoma Multiforme (GBM) cell apoptosis and cell-cycle arrest. MDM2-p53-IN-16 can be used for the cancer research.
    MDM2-p53-IN-16
  • HY-N0331
    Ziyuglycoside I
    		p53 Activator 99.42%
    Ziyuglycoside I isolated from S. officinalis root, has anti-wrinkle activity, and increases the expression of type I collagen. Ziyuglycoside I could be used as an active ingredient for cosmetics. Ziyuglycoside I triggers cell cycle arrest and apoptosis mediated by p53, it can be a potential agent candidate for treating triple-negative breast cancer (TNBC).
    Ziyuglycoside I
  • HY-117857
    MRT00033659
    		p53 Activator 99.77%
    MRT00033659 is a potent broad-spectrum kinase inhibitor of CK1 (IC50=0.9 μM for CK1δ) and CHK1 (IC50=0.23 μM). MRT00033659, a pyrazolo-pyridine analogue, induces p53 pathway activation and E2F-1 destabilisation.
    MRT00033659
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.