1. Apoptosis
  2. 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.

View MDM-2/p53 Pathway Map

MDM-2/p53 相关产品 (47):

Cat. No. Product Name Effect Purity
  • HY-15484
    Pifithrin-α hydrobromide p53 Inhibitor 98.28%
    Pifithrin-α hydrobromide是 p53 抑制剂,可阻断其转录活性并阻止细胞凋亡。
  • HY-15676
    RG7388 MDM2 Inhibitor 99.97%
    RG7388 是一种有效,选择性的 MDM2 拮抗剂,能够抑制 p53-MDM2 的结合,IC50 值为 6 nM。
  • HY-10029
    Nutlin 3a MDM2 Inhibitor 98.11%
    Nutlin 3a 是 Nutlin-3 的活性异构体,为一种鼠双微体 2 (MDM2) 拮抗剂,抑制 MDM2-p53 相互作用,且稳定 p53 蛋白,因此诱导细胞周期停滞和细胞凋亡。
  • HY-12296
    AMG 232 MDM2 Inhibitor 99.73%
    AMG 232 是一种有效,选择性,可口服的 p53-MDM2 相互作用抑制剂,IC50 值为 0.6 nM,与 MDM2 结合的 Kd 为 0.045 nM。
  • HY-50696
    Nutlin 3 MDM2 Inhibitor 98.32%
    Nutlin 3 是一种有效的 p53-MDM2 抑制剂,Ki 为 90 nM。
  • HY-101266
    Milademetan MDM2 Inhibitor
    Mliademetan 是 MDM2 的特异性抑制剂,是可用于治疗急性髓性白血病 (AML) 的药物成分。
  • HY-12734
    AM-8735 MDM2 Inhibitor
    AM-8735是有效,选择性的 MDM2 抑制剂,IC50 值为25 nM。
  • HY-10959
    RG7112 MDM2 Inhibitor 99.94%
    RG7112 是临床上第一个可口服的 MDM-2/p53 抑制剂,Kd 值为 11 nM。
  • HY-16702A
    Pifithrin-β hydrobromide p53 Inhibitor 99.90%
    Pifithrin-β是有效地p53抑制剂,IC50值为23 μM。
  • HY-15695
    Puromycin aminonucleoside p53 Activator 98.31%
    Puromycin aminonucleoside 是一种氨基核苷类抗生素,为嘌呤霉素类似物,但并不影响蛋白质合成或诱导凋亡。
  • HY-18986
    SAR405838 MDM2 Inhibitor 98.95%
    SAR405838是一种高效的选择性MDM2抑制剂, 与MDM2结合, Ki值为0.88 nM。
  • HY-18658
    NVP-HDM201 MDM2 Inhibitor 99.19%
    NVP-HDM201 (HDM201) 是高效,选择性,在临床I期试验中的 MDM-2/p53 抑制剂。
  • HY-19980
    PRIMA-1Met p53 Activator >99.0%
    PRIMA-1MET 是一种突变型 p53 复活剂,可恢复突变型 p53 的野生型构象和功能,并引发肿瘤细胞凋亡。PRIMA-1MET 还抑制硒蛋白硫氧还蛋白还原酶 1 (TrxR1)。
  • HY-15954
    NVP-CGM097 MDM2 Inhibitor 98.32%
    NVP-CGM097 是一种有效的选择性 MDM2 抑制剂,作用于 hMDM2IC50 为 1.7±0.1 nM。
  • HY-13424
    RITA p53 Activator
    RITA 是一种有效的 p53-HDM-2 相互作用抑制剂,可与 p53dN 结合,Kd 值为 1.5 nM,同时能够诱导 DNA-DNA 交联。
  • HY-P0121
    ReACp53 p53 Activator 99.65%
    ReACp53 能够抑制 p53 amyloid 的形成, 挽救 p53 在癌细胞中的作用。
  • HY-19980A
    PRIMA-1 p53 Activator >98.0%
    PRIMA-1 是一种突变型 p53 复活剂,可恢复 TP53 突变型甲状腺癌细胞对组蛋白甲基化抑制剂 3-Deazaneplanocin A 的敏感性。
  • HY-17493
    MI-773 MDM2 Inhibitor >98.0%
    MI-773 是一种 MDM2-p53 相互作用抑制剂,高亲和力结合到 MDM2Ki 为 0.88 nM。
  • HY-15510B
    Tenovin 6 Hydrochloride p53 Activator >98.0%
    Tenovin-6 Hydrochloride 是水溶的 SIRT1SIRT2 抑制剂,p53 的激活剂,同时能抑制 HDAC8 的活性,对 SirT1,SirT2,和 SirT3 的IC50 值分别为 21 μM,10 μM 和 67 μM。
  • HY-16664
    SJ-172550 MDM2 Inhibitor >98.0%
    SJ-172550是MDMX的小分子抑制剂; 与野生型p53肽竞争性结合于MDMX的EC50值为5 μM。
mdm-2-p53-map.png

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.

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