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-15676
    Idasanutlin MDM2 Inhibitor 99.90%
    Idasanutlin (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-12296
    AMG 232 MDM2 Inhibitor 99.90%
    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-15484
    Pifithrin-α hydrobromide p53 Inhibitor
    Pifithrin-α hydrobromide是 p53 抑制剂,可阻断其转录活性并阻止细胞凋亡。Pifithrin-α hydrobromide 同时为 aryl hydrocarbon receptor (AhR) 的激动剂。
  • HY-10029
    Nutlin-3a MDM2 Inhibitor 98.07%
    Nutlin-3a 是 Nutlin-3 的活性异构体,为一种鼠双微体 2 (MDM2) 抑制剂,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-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-128784
    PK11007 Activator 99.60%
    PK11007 是具有抗癌活性的温和硫醇烷基化剂。PK11007 通过两个表面暴露的半胱氨酸的选择性烷基化来稳定 p53,而不影响其 DNA 结合活性。PK11007 通过增加活性氧 (ROS) 水平诱导突变的 p53 癌细胞死亡。
  • HY-130684
    MDM2-IN-1 Inhibitor
    MDM2-IN-1 (Compound 30) 是一种合成的 MDM2-p53 相互作用 (MDM2) 抑制剂,包含反式 (D-)构型。
  • HY-123076
    Pifithrin-α, p-Nitro, Cyclic p53 Inhibitor
    Pifithrin-α, p-Nitro, Cyclic (PFN-α),是细胞通透性的 p53 抑制剂。Pifithrin-α, p-Nitro, Cyclic 对暴露于 Etoposide 的皮层神经元的保护作用比 Pifithrin-α 强一个数量级 (ED50=30 nM)。Pifithrin-α, p-Nitro, Cyclic 也作为 p53 转录后活性抑制剂。Pifithrin-α, p-Nitro, Cyclic 不阻止 p53 上的 S15 残基磷酸化。
  • 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-16702A
    Pifithrin-β hydrobromide p53 Inhibitor 99.90%
    Pifithrin-β hydrobromide (PFT β hydrobromide) 是有效地p53抑制剂,IC50值为23 μM。
  • HY-10959
    RG7112 MDM2 Inhibitor 99.91%
    RG7112 是有效的、选择性的、第一个用于临床的、可口服的、可透过血脑屏障的、 MDM2-p53 抑制剂,IC50 值为 18 nM,结合到MDM2 的KD 值为 11 nM.
  • HY-18658
    Siremadlin MDM2 Inhibitor 99.19%
    Siremadlin (NVP-HDM201) 是高效,选择性的 MDM-2/p53 抑制剂。
  • HY-10940
    Pifithrin-μ p53 Inhibitor 98.31%
    Pifithrin-μ 是一种 p53HSP70 的抑制剂,具有抗肿瘤和神经保护作用。
  • HY-13424
    RITA p53 Activator 99.57%
    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-18935A
    CBL0137 hydrochloride p53 Activator 98.25%
    CBL0137 hydrochloride 是组蛋白分子伴侣 FACT 的抑制剂。CBL0137 hydrochlorideye 也可以激活 p53 并抑制 NF-κB,对于它们的 EC50 值分别为 0.37 和 0.47 μM。
  • HY-15510
    Tenovin-6 p53 Activator 98.61%
    Tenovin-6 是一种 SIRT1SIRT2 抑制剂,p53 的激活剂,微弱抑制 HDAC8 的活性,对 SirT1 peptide deacetylase,SirT2 和 SirT3 的 IC50 值分别为 21 μM,10 μM 和 67 μM。
  • 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-18986
    SAR405838 MDM2 Inhibitor
    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-19896
    COTI-2 p53 Activator 99.40%
    COTI-2,一种具有口服活性的,低毒的抗癌药物,是一种第三代 p53 突变体 (p53 mutant) 的激活剂。COTI-2 通过激活突变型 p53 和抑制 PI3K/AKT/mTOR 途径发挥作用。COTI-2 诱导多种人肿瘤细胞凋亡 (apoptosis)。COTI-2 通过 p53 依赖和非依赖机制在 HNSCC 中具有抗肿瘤活性。COTI-2 将突变型 p53 转化为野生型构象。
  • HY-19980A
    PRIMA-1 p53 Activator >98.0%
    PRIMA-1 (NSC-281668) 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。

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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