1. Signaling Pathways
  2. Apoptosis
  3. MDM-2/p53

MDM-2/p53

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-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-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-U00441
    DPBQ
    p53 Activator 99.02%
    DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. DPBQ elicits expression and phosphorylation of p53 and this effect is specific to tetraploid cells.
    DPBQ
  • HY-B0860S
    Diuron-d6
    Activator 99.00%
    Diuron-d6 is the deuterium labeled Diuron (HY-B0860). Diuron is an orally active phenylurea herbicide. Diuron inhibits photosynthesis in plants by blocking the formation of ATP and NADH. Diuron increases the production of ROS. Diuron increases expression of p53 in certain cell lines. Diuron has herbicidal activity against annual and perennial broadleaf weeds and grass weeds. Diuron promotes DMBA/BBN-induced bladder cancer. Diuron can be used in breast cancer research.
    Diuron-d<sub>6</sub>
  • 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-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-163083
    JN122
    Inhibitor
    JN122, a spiroindoline-containing molecule, is a MDM2 inhibitor. JN122 Inhibits MDM2/p53 protein–protein interaction and exerts robust in vivo antitumor efficacy. JN122 has antiproliferative activity in HCT-116 cells and HEK-293 cells with IC50 values of 39.6 nM and 4.28μM, respectively. JN122 can promote activation of p53 and its target genes, inhibited cell cycle progression, and induced cell apoptosis.
    JN122
  • 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-18343
    CP-31398
    p53 Activator
    CP-31398 can stabilize the active conformation of p53 and promote p53 activity in cancer cells with either mutant or wild-type p53. In addition, CP-31398 can upregulate p53 target genes, such as p21WAF1/Cip1 and KILLER/DR5. CP-31398 exerts an inhibitory effect on tumor growth.
    CP-31398
  • HY-141584
    ATSP-7041
    MDM2 Inhibitor
    ATSP-7041, a selective dual peptide inhibitor of MDM2 and MDMX, effectively reactivates the p53 tumor suppressor pathway in a mechanism-dependent manner in p53-positive cancers.
    ATSP-7041
  • HY-101266A
    Milademetan tosylate
    MDM2 Inhibitor
    Milademetan tosylate is the tosylate salt form of Milademetan (HY-101266). Milademetan tosylate is an orally active inhibitor for MDM2. Milademetan tosylate arrests the cell cycle at G1 pahse, induces the apoptosis Milademetan tosylate restores the p53 activity by targeting the p53-MDM2 interaction, and exhibits anticancer activity against Merkel cell carcinoma (MCC).
    Milademetan tosylate
  • HY-112816
    MA242
    MDM2 Inhibitor
    MA242 is a specific dual inhibitor of MDM2 and NFAT1. MA242 directly binds both MDM2 and NFAT1 with high affinity, induces their protein degradation, and inhibits NFAT1-mediated transcription of MDM2. MA242 induces apoptosis in pancreatic cancer cell lines regardless of p53 status.
    MA242
  • HY-P5910A
    Azurin p28 peptide TFA
    Azurin p28 peptide TFA is a tumor-penetrated antitumor peptide. Azurin p28 peptide TFA redues proteasomal degradation of p53 through formation of a p28: p53 complex. Azurin p28 peptide TFA induces apoptosis or cell cycle arrest. Azurin p28 peptide TFA inhibits p53-positive tumor growths. Azurin p28 peptide TFA shows antiangiogenic effect by inhibiting phosphorylation of VEGFR-2, FAK and Akt.
    Azurin p28 peptide TFA
  • HY-173177
    PSF-IN-2
    Activator
    PSF-IN-2 (Compound (C)-30) is a PSF inhibitor with an IC50 value of 0.005 pM. PSF-IN-2 exhibits anti-cancer activity, and its IC50 value for inhibiting the proliferation of 22Rv1 cells is 0.5 μM. PSF-IN-2 activates the p53 signaling pathway by inhibiting the binding of PSF to RNA, inducing the expression of related genes, promoting apoptosis, and inhibiting the cell cycle. PSF-IN-2 can be used in cancer research.
    PSF-IN-2
  • HY-13705
    NM-3
    NM-3 is an isocoumarin with antiarthritic and antiangiogenic effects. NM-3 is an orally active antiangiogenic agent with low toxicity.
    NM-3
  • HY-172204
    SIRT-IN-7
    Activator
    SIRT-IN-7 (Compound 7ba) is a SIRT inhibitor. SIRT-IN-7 can inhibit the expression of SIRT1, SIRT2, and SIRT3, and increase the acetylation and activation of p53. SIRT-IN-7 can inhibit the proliferation, and induce apoptosis and autophagy of breast cancer cells. SIRT-IN-7 has anti-tumor activity.
    SIRT-IN-7
  • HY-163357
    CDK2/MDM2-IN-1
    Inhibitor
    CDK2/MDM2-IN-1 (III-13) is a dual inhibitor of CDK2/MDM2 with an IC50 value of 2.60 nM for CDK2. CDK2/MDM2-IN-1 has antitumor activity.
    CDK2/MDM2-IN-1
  • HY-113843
    RETRA hydrobromide
    Activator
    RETRA (hydrobromide) is a mutant p53-dependent activator of p73 that can inhibit cancer cells carrying mutant p53. RETRA (hydrobromide) increases the expression level of p73, induces transcriptional activation of several common to transcriptional targets p53 and p73, which leads to mutant p53- and p73-dependent inhibition of tumor growth, reduction of colony formation and induction of effector caspases.
    RETRA hydrobromide
Cat. No. Product Name / Synonyms Application Reactivity

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.