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-101518
    Alrizomadlin
    		MDM2 Inhibitor 98.67%
    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.
    Alrizomadlin
  • HY-16702A
    Pifithrin-β hydrobromide
    		p53 Inhibitor 99.97%
    Pifithrin-β hydrobromide (PFT β hydrobromide) is a potent p53 inhibitor with an IC50 of 23 μM.
    Pifithrin-β hydrobromide
  • 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.
    Kevetrin hydrochloride
  • HY-N2037A
    Higenamine hydrochloride
    		Activator 99.68%
    Higenamine hydrochloride is a selective LSD1 inhibitor (IC50=1.47 μM) that can be isolated from aconite. Higenamine hydrochloride has anti-inflammatory and antibacterial activity. Higenamine (Norcoclaurine) can attenuate IL-1β-induced Apoptosis through ROS-mediated PI3K/Akt signaling pathway. Higenamine hydrochloride protects brain cells from oxygen deprivation. Higenamine can promote bone formation in osteoporosis through the SMAD2/3 pathway. Higenamine hydrochloride can be used to study cancer, inflammation, cardiorenal syndrome and other diseases.
    Higenamine hydrochloride
  • HY-13424
    RITA
    		p53 Activator 99.45%
    RITA is an inhibitor of p53-HDM-2 interaction, binds to p53dN, with a Kd of 1.5 nM, and also induces DNA-DNA cross-links.
    RITA
  • HY-19896
    COTI-2
    		p53 Activator 99.66%
    COTI-2, an anti-cancer agent with low toxicity, is an orally available third generation activator of p53 mutant forms. COTI-2 acts both by reactivating mutant p53 and inhibiting the PI3K/AKT/mTOR pathway. COTI-2 induces apoptosis in multiple human tumor cell lines. COTI-2 exhibits antitumor activity in HNSCC through p53-dependent and -independent mechanisms. COTI-2 converts mutant p53 to wild-type conformation.
    COTI-2
  • HY-15954
    NVP-CGM097
    		MDM2 Inhibitor 98.06%
    NVP-CGM097 is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.
    NVP-CGM097
  • HY-110182
    SP-141
    		MDM2 Inhibitor 99.94%
    SP-141 is a specific inhibitor of MDM2. SP-141 promotes MDM2 auto-ubiquitination and degradation. SP-141 might be used for the research of pancreatic cancer and breast cancer cells.
    SP-141
  • HY-148416
    p53 Activator 7
    		p53 Activator 98.52%
    p53 Activator 7 is a p53 mutation Y220C (MDM-2/p53) activator with an EC50 of 104 nM. p53 Activator 7 can bind to p53 mutant and restore its ability to bind DNA (WO2022213975A1; Example B-1). p53 Activator 7 is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
    p53 Activator 7
  • HY-19980A
    PRIMA-1
    		p53 Activator ≥98.0%
    PRIMA-1 (NSC-281668) is a mutant p53 reactivator, restores the sensitivity of TP53 mutant-type thyroid cancer cells to the histone methylation inhibitor 3-Deazaneplanocin A.
    PRIMA-1
  • HY-18986
    SAR405838
    		MDM2 Inhibitor 99.19%
    SAR405838 (MI-77301), an analog of MI-773, is a highly potent and selective MDM2-p53 interaction inhibitor. SAR405838 binds to MDM2 with a Ki of 0.88 nM. SAR405838 induces apoptosis and has potent antitumor activity.
    SAR405838
  • HY-B0294
    Flubendazole
    		Activator 99.01%
    Flubendazole is an anthelmintic drug based on altering microtubule structure, inhibition of tubulin polymerization and disruption of microtubule function. Flubendazole induces apoptosis in human colorectal cancer (CRC) by blocking the STAT3 signaling axis and activation of autophagy. Flubendazole induces P53 expression and reduced Cyclin B1 and p-cdc2 expression. Flubendazole is an antitumor agent. Flubendazole can be used for worm and intestinal parasites.
    Flubendazole
  • HY-12025
    Serdemetan
    		MDM2 Inhibitor 99.81%
    Serdemetan(JNJ-26854165) acts as a HDM2 ubiquitin ligase antagonist and also induces early apoptosis in p53 wild-type cells, inhibits cellular proliferation followed by delayed apoptosis in the absence of functional p53.
    Serdemetan
  • HY-P4210
    Sulanemadlin
    		Inhibitor
    Sulanemadlin (ALRN-6924) is a potent and cell-permeating p53-based peptidomimetic macrocycles. Sulanemadlin is a inhibitor of the p53-MDM2, p53-MDMX, or both p53 and MDM2 and MDMX protein-protein interactions. Sulanemadlin can be used for cancers research.
    Sulanemadlin
  • HY-18343A
    CP-31398 dihydrochloride
    		p53 Activator 98.29%
    CP-31398 dihydrochloride stabilizes the active conformation of p53 and promotes p53 activity in cancer cell lines with mutant or wild-type p53.
    CP-31398 dihydrochloride
  • HY-15510
    Tenovin-6
    		p53 Activator 98.33%
    Tenovin-6, an analog of Tenovin-1 (HY-13423), is an activator of p53 transcriptional activity. Tenovin-6 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 also inhibits dihydroorotate dehydrogenase (DHODH).
    Tenovin-6
  • HY-N0068
    Solasodine
    		MDM2 Inhibitor 99.54%
    Solasodine (Purapuridine) is a steroidal alkaloid that occurs in plants of the Solanaceae family. Solasodine has neuroprotective, antifungal, hypotensive, anticancer, antiatherosclerotic, antiandrogenic and anti-inflammatory activities.
    Solasodine
  • HY-148409
    MMRi62
    		Inhibitor 99.58%
    MMRi62, a ferroptosis inducer targeting MDM2-MDM4 (negative regulators of tumor suppressor p53). MMRi62 shows a P53-independent pro-apoptotic activity against pancreatic ductal adenocarcinoma (PDAC) cells and induce autophagy. MMRi62 inducesferroptosis, resulting in a increase of reactive oxygen and lysosomal degradation of ferritin heavy chain (FTH1). MMRi62 also leads to proteasomal degradation of mutant p53, also inhibits orthotopic xenograft PDAC mouse model in vivo with high frequency mutation characteristics of KRAS and TP53.12.
    MMRi62
  • HY-110088
    SCH529074
    		Activator 99.73%
    SCH529074 is a potent and orally active p53 activator. SCH529074 binds specifically and conformation-dependently to p53 DBD ( DNA binding domain) with a Ki of 1-2 μM in a saturable manner. SCH529074 restores mutant p53 function and interrupts HDM2-mediated ubiquitination of wild Type p53. SCH529074 can be used for the study of non-small-cell lung carcinoma (NSCLC).
    SCH529074
  • HY-108637
    PhiKan 083
    		p53 Activator ≥98.0%
    PhiKan 083 is a carbazole derivative, which binds to the surface cavity and stabilizes Y220C (a p53 mutant), with a Kd of 167 μM. PhiKan 083 can be used for cancer research.
    PhiKan 083
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.