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
  • HY-10029
    Nutlin-3a
    MDM2 Inhibitor 98.07%
    Nutlin-3a (Rebemadlin), an active enantiomer of Nutlin-3, is a potent murine double minute (MDM2) inhibitor (IC50=90 nM). Nutlin-3a inhibits MDM2-p53 interactions and stabilizes the p53 protein, and induces cell autophagy and apoptosis. Nutlin-3a has the potential for the study of TP53 wild-type ovarian carcinomas.
  • HY-17412
    Minocycline hydrochloride
    p53 Activator 99.79%
    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.
  • HY-15676
    Idasanutlin
    MDM2 Inhibitor 99.90%
    Idasanutlin (RG7388) is a potent and selective MDM2 antagonist, inhibiting p53-MDM2 binding, with an IC50 of 6 nM.
  • HY-15484
    Pifithrin-α hydrobromide
    p53 Inhibitor 98.05%
    Pifithrin-α hydrobromide is a p53 inhibitor which blocks its transcriptional activity and prevents cells from apoptosis. Pifithrin-α hydrobromide is also an aryl hydrocarbon receptor (AhR) agonist.
  • HY-12296
    Navtemadlin
    MDM2 Inhibitor 99.43%
    Navtemadlin (AMG 232) is a potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC50 of 0.6 nM. Navtemadlin binds to MDM2 with a Kd of 0.045 nM.
  • HY-103640
    Amifostine thiol dihydrochloride
    p53 Activator ≥98.0%
    Amifostine thiol (WR-1065) dihydrochloride can protect normal tissues from the toxic effects of certain cancer drugs and activate p53 through a JNK-dependent signaling pathway.
  • HY-16271
    Kevetrin hydrochloride
    p53 Activator ≥98.0%
    Kevetrin hydrochloride is a potent activator of p53, induces apoptosis in TP53 wild-type and mutant acute myeloid leukemia cells. Kevetrin a preferential cytotoxic activity against blast cells.
  • HY-W042191
    Oxychlororaphine
    Inducer
    Oxychloroaphine could be isolated from the bacterium Pantoea agglomerans naturally present in soil. Oxychloroaphine has broad-spectrum antifungal activity. Oxychloroaphine has cytotoxicity in a dose-dependent manner and induces apoptosis. Oxychloroaphine can be used in research of cancer.
  • HY-50696
    Nutlin-3
    MDM2 Inhibitor 99.18%
    Nutlin-3 is a commercial available p53-MDM2 inhibitor, with Ki of 90 nM.
  • HY-19980
    Eprenetapopt
    p53 Activator ≥99.0%
    Eprenetapopt (APR-246) is a first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. Eprenetapopt triggers apoptosis in tumor cells. Eprenetapopt also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance.
  • HY-10959
    RG7112
    MDM2 Inhibitor 99.91%
    RG7112 is a potent, selective, first clinical, orally active and blood-brain barrier crossed MDM2-p53 inhibitor, with an IC50 of 18 nM and a KD of 11 nM for binding to MDM2.
  • HY-18935A
    CBL0137 hydrochloride
    p53 Activator 99.66%
    CBL0137 hydrochloride is an inhibitor of the histone chaperone, FACT. CBL0137 hydrochloride can also activate p53 and inhibits NF-κB with EC50s of 0.37 and 0.47 µM, respectively.
  • HY-18658
    Siremadlin
    MDM2 Inhibitor 99.82%
    Siremadlin (NVP-HDM201) is a potent, orally bioavailable and highly specific p53-MDM2 interaction inhibitor.
  • HY-123076
    Pifithrin-α, p-Nitro, Cyclic
    p53 Inhibitor ≥99.0%
    Pifithrin-α, p-Nitro, Cyclic (PFN-α) is cell-permeable and active-form p53 inhibitor. Pifithrin-α, p-Nitro, Cyclic is one order magnitude more active than Pifithrin-α in protecting cortical neurons exposed to Etoposide (ED50=30 nM). Pifithrin-α, p-Nitro, Cyclic behaves as a p53 posttranscriptional activity inhibitor. Pifithrin-α, p-Nitro, Cyclic do not prevent p53 phosphorylation on the S15 residue.
  • HY-114312
    MD-224
    MDM2 Inhibitor 98.08%
    MD-224 is a first-in-class and highly potent small-molecule human murine double minute 2 (MDM2) degrader based on the proteolysistargeting chimera (PROTAC) concept. MD-224 consists of ligands for Cereblon and MDM2. MD-224 induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells, and achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells. MD-224 has the potential to be a new class of anticancer agent.
  • HY-B0639
    Amifostine
    p53 Activator ≥98.0%
    Amifostine (WR2721) is a broad-spectrum cytoprotective agent and a radioprotector. Amifostine selectively protects normal tissues from damage caused by radiation and chemotherapy. Amifostine is potent hypoxia-inducible factor-α1 (HIF-α1) and p53 inducer. Amifostine protects cells from damage by scavenging oxygen-derived free radicals. Amifostine reduces renal toxicity and has antiangiogenic action.
  • HY-101266
    Milademetan
    MDM2 Inhibitor 98.77%
    Milademetan (DS-3032) is a specific and orally active MDM2 inhibitor for the research of acute myeloid leukemia (AML) or solid tumors. Milademetan (DS-3032) induces G1 cell cycle arrest, senescence and apoptosis.
  • HY-101518
    Alrizomadlin
    MDM2 Inhibitor 98.16%
    Alrizomadlin (APG-115) is an orally active MDM2 protein inhibitor binding to MDM2 protein with IC50 and Ki values of 3.8 nM and 1 nM, respectively. Alrizomadlin blocks the interaction of MDM2 and p53 and induces cell-cycle arrest and apoptosis in a p53-dependent manner.
  • HY-112780
    UC2288
    Inhibitor 99.92%
    UC2288 is a novel, cell-permeable, and orally active p21 attenuator (relatively selective activity for p21), which is synthesized based Sorafenib (HY-10201). UC2288 decreases p21 mRNA expression independently of p53, and attenuates p21 protein levels with minimal effect on p21 protein stability. UC2288 has no inhibition of VEGFR2 and Raf kinases even at 10 μM.
  • HY-10940
    Pifithrin-μ
    p53 Inhibitor 99.53%
    Pifithrin-μ is an inhibitor of p53 and HSP70, with antitumor and neuroprotective activity.

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.