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-P5343
    p53 CBS
    p53 CBS (p53 Consensus binding sequence) is a biological active peptide. (p53 consensus DNA binding site)
    p53 CBS
  • HY-145907
    p53-HDM2-IN-1
    		Inhibitor
    p53-HDM2-IN-1 is a potent inhibitor of p53-HDM2 protein-protein interaction, with an IC50 of 0.103 μM. p53-HDM2-IN-1 can be used for the research of cancer.
    p53-HDM2-IN-1
  • HY-133760
    MI-888
    		Inhibitor
    MI-888 is an orally active MDM2 inhibitor with a Ki of 0.44 nM. MI-888 can inhibit the MDM2-p53 interaction. MI-888 has favorable pharmacokinetic properties and anti-tumor activity.
    MI-888
  • HY-123950
    MMRi64
    		Inhibitor ≥98.0%
    MMRi64 disrupts Mdm2-MdmX interactions. MMRi64 downregulates Mdm2 and MdmX in leukemia cells. MMRi64 induces p53 accumulation, and induces the apoptotic arm of the p53 pathway in leukemia/lymphoma cells. MMRi64 can be used for cancer research.
    MMRi64
  • HY-170595
    PROTAC LZK-IN-1
    		Inhibitor
    PROTAC LZK-IN-1 (Compound 21A) is a PROTAC that targets the degradation of LZK (Leucine Zipper Kinase, encoded by MAP3K13). PROTAC LZK-IN-1 (10 μM) promotes the degradation of LZK and inhibits the expression of p53 and c-MYC, leading to reduced viability of global head and neck squamous cell carcinoma (HNSCC) cell lines. PROTAC LZK-IN-1 can be used in cancer research. PROTAC LZK-IN-1 consists of an E3 ligase ligand (blue part, HY-112078), a target protein ligand (red part, HY-170596), and a linker (black part, HY-W019543)[1].
    PROTAC LZK-IN-1
  • HY-168636
    p53 Activator 13
    		Activator
    p53 Activator 13 (compound 11) is a 6mA methyltransferase CamA inhibitor and a p53 activator. p53 Activator 13 intercalates into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA and elicits DNA damage response via p53 activation. p53 Activator 13 can be utilized in cancer research.
    p53 Activator 13
  • HY-146806
    YL93
    		Inhibitor
    YL93 is a dual inhibitors of MDM2/4 with Ki values of 0.64 μM and 1.1 nM for MDM4 and MDM2, respectively. YL93 induces cell-cycle arrest and apoptosis. YL93 shows p53-dependent cell growth inhibition.
    YL93
  • HY-151169
    MDM2/4-p53-IN-1
    		MDM2 Inhibitor
    MDM2/4-p53-IN-1 is a potent MDM2-p53 and MDM4-p53 inhibitor with IC50 values of 35.9, 57.4 nM, respectively. MDM2/4-p53-IN-1 shows antiproliferative activity.
    MDM2/4-p53-IN-1
  • HY-16271S
    Kevetrin hydrochloride-13C2,15N3
    		p53 Activator
    Kevetrin (hydrochloride)-13C2,15N3 is the 13C-labeled and 15N-labeled Kevetrin (hydrochloride). Kevetrin hydrochloride is a small molecule and activator of the tumor suppressor protein p53, with potential antineoplastic activity.
    Kevetrin hydrochloride-<sup>13</sup>C<sub>2</sub>,<sup>15</sup>N<sub>3</sub>
  • HY-Y0148R
    10-Hydroxydecanoic acid (Standard)
    10-Hydroxydecanoic acid (Standard) is the analytical standard of 10-Hydroxydecanoic acid. This product is intended for research and analytical applications. 10-Hydroxydecanoic acid (10-HDAA) is a saturated fatty acid derived from 10-hydroxy-trans-2-decenoic acid, which can be isolated from royal jelly. 10-Hydroxydecanoic acid exhibits various biological activities, including anti-inflammatory, insecticidal, anti-malarial, and anti-Leishmania properties, as well as enhancing antigen-specific immune responses. The anti-inflammatory effects of 10-Hydroxydecanoic acid are primarily mediated by inhibiting the activation of NF-κB and the translation of interferon regulatory factor 1 (IRF-1), which reduces the production of interleukin 6 (IL-6) and nitric oxide (NO) in inflammatory cells. Additionally, 10-Hydroxydecanoic acid alleviates neuroinflammatory responses through the p53-autophagy pathway and the p53-NLRP3 pathway. Finally, 10-Hydroxydecanoic acid enhances antigen-specific immune responses by promoting the effective uptake of antigens by microfold cells[1][2][3][4][5].
    10-Hydroxydecanoic acid (Standard)
  • HY-153200
    MDM2/XIAP-IN-2
    		Inhibitor
    MDM2/XIAP-IN-2 is a dual inhibitor of murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP). MDM2/XIAP-IN-2 degrades MDM2, and inhibits XIAP mRNA translation to inhibits cancer cells. Particularly, MDM2/XIAP-IN-2 inhibits acute lymphoblastic leukemia cell line EU-1 with an IC50 value of 0.3 μM.
    MDM2/XIAP-IN-2
  • HY-161040
    MDM2-p53-IN-19
    		Inhibitor
    MDM2-p53-IN-19 (Compound A-8d) is a chemical intermediate that can be used to synthesize inhibitors of the MDM2-p53 interaction with anticancer activity.
    MDM2-p53-IN-19
  • HY-122646
    USP7-IN-2
    		MDM2 Inhibitor
    USP7-IN-2 (compound 4) is a non-competitive USP7 inhibitor with an IC50 of 6 nM. USP7-IN-2 causes degradation of MDM2, stabilization of p53 and induction of p21 in multiple cell lines, and can be utilized in cancer research.
    USP7-IN-2
  • HY-144791
    Bcl-2-IN-6
    		p53 Activator
    Bcl-2-IN-6 (compound 10) is a potent Bcl-2 (B-cell lymphoma-2) inhibitor. Bcl-2-IN-7 down-regulates the expression of Bcl-2, and increases the expression of p53, Bax, and caspase-7 mRNA. Bcl-2-IN-7 induces cell cycle arrest and apoptosis in breast cancer MCF-7 cells. Bcl-2-IN-7 shows good anticancer activity, with IC50 values of 20.91, 22.30, 42.29, and 48.00 μM against MCF-7, LoVo, HepG2, and A549 cell lines, respectively.
    Bcl-2-IN-6
  • HY-W013053R
    Dibenz[a,h]anthracene (Standard)
    Dibenz[a,h]anthracene (Standard) is the analytical standard of Dibenz[a,h]anthracene. This product is intended for research and analytical applications. 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 (Standard)
  • HY-P10914
    D-CopA3
    		MDM2 Inhibitor
    D-CopA3 is the inhibitor for MDM2 and the activator for p53 signaling pathway. D-CopA3 exhibits cytotoxicity in colorectal cancer cells HCT-116, LoVo, and RKO (IC50=15-18 μM), induces JNK/Beclin-1 mediated autophagy. D-CopA3 downregulates the expression of cell cycle inhibitory protein p21Cip1/Waf1, enhances the mucosal barrier function and reduces penetration of inflammatory mediators. D-CopA3 exhibits anti-inflammtory activity in mouse C. difficile toxin A-induced acute enteritis models and DSS (HY-116282)-induced chronic colitis models. D-CopA3 exhibits antitumor efficacy in mouse HCT-116 xenograft models.
    D-CopA3
  • HY-158685
    RG7112D
    		MDM2 Inhibitor
    RG7112D is a potent MDM2 inhibitor with IC50s of 11 nM and >10000 nM and for MDM2-p53 and VHL-HIF1α by binding HTRF assay, respectively. RG7112D is coupled by an amide bond to VHL-Amine, resulting in a bi-functional molecule, YX-02-030. YX-02-03, a MDM2-PROTAC, potently inhibits MDM2-p53 binding (HTRF IC50=63nM). RG7112D can stabilize MDM2 protein and increase p53 protein levels.
    RG7112D
  • HY-153199
    MDM2/XIAP-IN-1
    		Inhibitor
    MDM2/XIAP-IN-1 (compound 14) is an orally active inhibitor of dual MDM2/XIAP. MDM2/XIAP-IN-1 has anti-cancer activity with an IC50 value of 0.3 μM, which can be used in cance rescrch.
    MDM2/XIAP-IN-1
  • HY-N0331R
    Ziyuglycoside I (Standard)
    		p53 Activator
    Ziyuglycoside I (Standard) is the analytical standard of Ziyuglycoside I. This product is intended for research and analytical applications. 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 (Standard)
  • HY-173074
    Microtubulin-IN-1
    		p53 Activator
    Microtubulin-IN-1 (Compound 8g) is the inhibitor for microtubulin that targets colchicine-binding site, disrupts the microtubulin integrity, and induces the upregulation of p53. Microtubulin-IN-1 exhibits antiproliferative activity in a variety of cancer cell lines (IC50 for NCI-H460, BxPC-3 and HT-29 is 2.4, 1.6 and 2.07 nM, respectively), arrests the cell cycle at G2/M phase, and induces apoptosis in NCI-H460.
    Microtubulin-IN-1
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.