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-158328A
    CA IX/VEGFR-2-IN-2
    		Activator
    CA IX/VEGFR-2-IN-2 (compound 5e) is a dual-targeted inhibitor. CA IX/VEGFR-2-IN-2 shows strong inhibitory effects on both CA IX (Ki=3.1 μM) and VEGFR-2 (IC50=32.1 nM). CA IX/VEGFR-2-IN-2 can be used for the study of pancreatic (PANC1), breast cancer (MCF7) and prostate cancer (PC3) .
    CA IX/VEGFR-2-IN-2
  • HY-W710827
    N,N'-Methylenebisacrylamide-d6
    N,N'-Methylenebisacrylamide-d6 is the deuterium labeled N,N'-Methylenebisacrylamide (HY-D0848). N,N'-Methylenebisacrylamide (Bisacrylamide) is an orally active acrylamide dimer and crosslinker. N,N'-Methylenebisacrylamide increases CYP2E1, P53, cleaved caspase-3. N,N'-Methylenebisacrylamide promotes hepatic cancer. N,N'-Methylenebisacrylamide changes sperm abnormality rate and sperm count. N,N'-Methylenebisacrylamide decreases the number of various cells in the blood as well as induces liver and testicular damage. N,N'-Methylenebisacrylamide is used to prepare polyacrylamide gel.
    N,N'-Methylenebisacrylamide-d<sub>6</sub>
  • HY-P10295
    p53 (232-240)
    p53 (232-240) is a peptide segment of the 232-240 amino acid sequence of the human tumor suppressor protein p53. p53 (232-240) enhances its binding affinity to the Major histocompatibility complex (MHC), thereby enhancing the immunogenicity of this peptide to enhance the immune system's response to tumor antigens. p53 (232-240) can be used in the development of cancer vaccines and in the study of tumor cell recognition and clearance by the immune system.
    p53 (232-240)
  • HY-168623
    EGFR-IN-134
    		Activator
    EGFR-IN-134 (compound 3f), a triazolo[3,4-a]isoquinoline derivative, is a potent EGFR inhibitor with an IC50 of 0.023 µM. EGFR-IN-134 induces apoptosis and necrosis. EGFR-IN-134 initiates cell cycle arrest at the G2/M and pre-G1 phases, downregulates anti-apoptotic protein Bcl2 and upregulates pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. EGFR-IN-134 shows antiproliferative and anticancer activity.
    EGFR-IN-134
  • HY-119053
    MS7972
    		p53 Inhibitor 99.81%
    MS7972 is a small molecule that blocks human p53 and CREB binding protein association. MS7972 can almost completely block this BRD interaction at 50 μM.
    MS7972
  • HY-107466
    WK298
    WK298 is a potent inhibitor of the MDM2/MDMX-p53 interaction with good anti-tumor activity. WK298 can fully activate the p53 pathway by inhibiting the binding of MDM2 and MDMX to p53. The development of WK298 benefited from a deep understanding of the key elements of the p53-MDM2/MDMX interaction structure.
    WK298
  • HY-147783
    Anticancer agent 68
    Anticancer agent 68 is (Compound 12) is an anti-cancer agent. Anticancer agent 68 arrests the cells at the G2/M phase and induces programmed cell death. Anticancer agent 68 induces upregulation of tumor suppression via activation of p53 & PTEN.
    Anticancer agent 68
  • HY-169327
    MD-265
    		Degrader
    MD-265 is a PROTAC degrader that can break down MDM2, leading to activation of p53 in cancer cells carrying wild-type p53. MD-265 achieves complete tumor regression and improves long-term survival of mice with leukemia. (Pink: MI-1063 (HY-133754); Black: linker; Blue: Lenalidomide (HY-A0003).
    MD-265
  • HY-N0171AR
    Beta-Sitosterol (purity>98%) (Standard)
    		Agonist
    Beta-Sitosterol (purity>98%) (Standard) is an analytical standard for Beta-Sitosterol (purity>98%). Beta-Sitosterol (purity>98%) is intended for research and analytical applications. Beta-Sitosterol (purity>98%) is orally active. Beta-Sitosterol exhibits multiple activities, including anti-inflammatory, anticancer, antioxidant, antimicrobial, antidiabetic, antioxidant enzyme, and analgesic. Beta-Sitosterol inhibits inflammation and impaired adipogenesis in bovine mammary epithelial cells by reducing levels of ROS, TNF-α, IL-1β, and NF-κB p65 and restoring the activity of the HIF-1α/mTOR signaling pathway. Beta-Sitosterol induces apoptosis in cancer cells through ROS-mediated mitochondrial dysregulation and p53 activation. Beta-Sitosterol exerts its anticancer effects in cancer cells by activating caspase-3, caspase-8, and caspase-9, mediating PARP inactivation, MMP loss, altered Bcl-2-Bax ratio, and cytochrome c release. Beta-Sitosterol modulates macrophage polarization and reduces rheumatoid inflammation in mice. Beta-Sitosterol inhibits tumor growth in multiple mouse cancer models. Beta-Sitosterol can be used in the research of arthritis, lung cancer, breast cancer and other cancers, diabetes, etc.
    Beta-Sitosterol (purity>98%) (Standard)
  • HY-145670
    cis,trans-Germacrone
    		Inhibitor
    cis,trans-Germacrone is a isomer of Germacrone (HY-N0440). Germacrone exhibits a wide range of antitumor, antioxidant and anti-inflammatory effects. Germacrone inhibits lung cancer cell proliferation and alters the Akt/MDM2/p53. Germacrone also arrests cell cycle at G1/S phase.
    cis,trans-Germacrone
  • HY-125858B
    (S,R,S)-MI-1061
    		Control
    (S,R,S)-MI-1061 is the isomer of MI-1061(HY-125858). (S,R,S)-MI-1061 can used to synthesize Antibody-Drug Conjugates (ADCs). MI-1061 is a potent, orally bioavailable, and chemically stable MDM2 (MDM2-p53 interaction) inhibitor (IC50=4.4 nM; Ki=0.16 nM). MI-1061 potently activates p53 and induces apoptosis in the SJSA-1 xenograft tumor tissue in mice. Anti-tumor activity.
    (S,R,S)-MI-1061
  • HY-174266
    WB156
    		Degrader
    WB156 is a dual MDM2 and GSPT1 degrader. WB156 can recruit CRBN (Cereblon, a substrate receptor of the E3 ubiquitin-ligase complex) to induce the ubiquitination-proteasome pathway-mediated degradation of MDM2 and GSPT1. WB156 is promising for research of cancers, such as leukemia.
    WB156
  • HY-175848
    NSC 850745
    		p53 Activator
    NSC 850745 is a selective and potent c-Met/STAT3 inhibitor with IC50 values of 210 and 670 nM. NSC 850745 can inhibit cell proliferation, induce G2/M phase arrest and induce apoptosis. NSC 850745 can downregulate AKT-1, VEGF and Bcl-2 expression and upregulate p53, Bax and caspase expression. NSC 850745 can be used for the research of cancer, such as leukemia and colon cancer.
    NSC 850745
  • HY-B0639C
    Amifostine sodium
    		p53 Activator
    Amifostine sodium (WR2721 sodium) is a phosphorus sulfate with radioprotective activity. Amifostine sodium can cause splenic vasodilation and may block autonomic ganglia. Amifostine sodium is clinically used to prevent cisplatin-induced ototoxicity.
    Amifostine sodium
  • HY-P10780
    RFRP-3 (mouse)
    		Activator
    RFRP-3 (mouse) is a functional ortholog of avian gonadotropin inhibitory hormone (GnIH), binding to GPR147. RFRP-3 (mouse) reduces Progesterone synthesis by inhibiting FSHR and key enzymes involved in steroidogenesis (P450scc, 3β-HSD, StAR). RFRP-3 (mouse) induces Apoptosis (increase of p53). RFRP-3 (mouse) also suppresses the ERK signaling pathway. RFRP-3 (mouse) can be used for research of follicular development.
    RFRP-3 (mouse)
  • HY-122038
    NU-8165
    NU-8165 is an inhibitor of the MDM2-p53 protein-protein interaction with anti-tumor activity. Optimization of NU-8165 was guided by MDM2 NMR titrations, which indicated key binding interaction regions. NU-8165 activated MDM2 and p21 transcription in cell-based assays and showed modest selectivity for wild-type p53 cell lines.
    NU-8165
  • HY-103640R
    Amifostine thiol dihydrochloride (Standard)
    		p53 Activator
    Amifostine thiol (dihydrochloride) (Standard) is the analytical standard of Amifostine thiol (dihydrochloride). This product is intended for research and analytical applications. Amifostine thiol (WR-1065) dihydrochloride can protect normal tissues from the toxic effects of certain cancer agents and activate p53 through a JNK-dependent signaling pathway.
    Amifostine thiol dihydrochloride (Standard)
  • HY-159938
    p38α inhibitor 6
    		p53 Activator
    p38α inhibitor 6 (compound 19) is a p38α inhibitor with the IC50 of 0.68 μM. p38α inhibitor 6 induces cell apoptosis and arrests cell cycle at G0 and G2/M phase. p38α inhibitor 6 decreases the TNF-α concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.
    p38α inhibitor 6
  • HY-172915
    p53 Stabilizer 2
    		Modulator
    p53 Stabilizer 2 (Compound 17a16) is a p53 stabilizer. p53 Stabilizer 2 induces S-phase arrest and apoptosis in both p53-proficient and p53-deficient cancer cells. p53 Stabilizer 2 induces mitochondrial stress and activates two checkpoint pathways: NA-PKcs-dependent p53 stabilization and ATR-Chk1 axis activation. p53 Stabilizer 2 inhibits tumor growth in p53-deficient xenograft model.
    p53 Stabilizer 2
  • HY-18052
    AM-8553
    		Inhibitor
    AM-8553 is a MDM2/p53 inhibitor (KD: 0.4 nM for MDM2). AM-8553 has anti-tumor activity
    AM-8553
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.