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

MDM-2/p53 

p53 肿瘤抑制因子是响应多种细胞损伤而导致生长停滞、衰老和凋亡的主要介质。p53 是一种短寿命蛋白质，在正常细胞中维持在较低水平，通常无法检测到。在压力条件下，p53 蛋白在细胞中积累，以四聚体形式与 p53 反应元件结合并诱导各种基因的转录。

MDM-2 由 p53 转录激活，而 MDM-2 反过来以多种方式抑制 p53 活性。MDM-2 与 p53 转录激活域结合，从而抑制 p53 介导的转录激活。MDM-2 还包含类似于各种病毒蛋白的核输出信号的信号序列，在与 p53 结合后，它会诱导其核输出。由于 p53 是一种转录因子，它需要位于细胞核中才能接触 DNA； MDM-2 将其转运至细胞质可防止这种情况发生。最后，MDM-2 是一种泛素连接酶，因此能够靶向 p53 并由蛋白酶体降解。

在许多肿瘤中，p53 因负调节因子 MDM2 和 MDM4 的过度表达或 MDM2 抑制剂 ARF 的活性丧失而失活。这些肿瘤中的该通路可以通过抑制 MDM2 和/或 MDM4 与 p53 相互作用的小分子重新激活。此类分子目前正在临床试验中。

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-162450
    Antitumor agent-150 MDM2 Inhibitor
    Antitumor agent-150 (V10) 是一种抗乳腺癌剂，是 MDM2 的 PROTAC 降解剂（Red: Ganoderic acid A ; Black: 4O-PEG linker; Blue: VHL ligand）。
    Antitumor agent-150
  • HY-158151
    p53 Activator 12 Activator
    p53 Activator 12 (compound 510B) 是一种有效的 p53 激活剂。p53 Activator 12 可与突变型 p53 结合，并恢复 p53 突变体结合 DNA 的能力。
    p53 Activator 12
  • HY-161874
    RPS6-IN-1 Inducer
    RPS6-IN-1 (Compound 22o) 抑制细胞转移，诱导细胞凋亡 (Apoptosis) (增加 Bax、p53、cleaved-caspase 3 和 cleaved-PARP 的表达)。RPS6-IN-1 降低线粒体膜电位。RPS6-IN-1 通过 PI3K-Akt-mTOR 信号通路激活自噬 (Autophagy)，损伤细胞内线粒体和溶酶体，并引起内质网应激。RPS6-IN-1 抑制 RPS6 磷酸化。RPS6-IN-1 是一种全身毒性较低的抗癌剂。
    RPS6-IN-1
  • HY-147783
    Anticancer agent 68
    Anticancer agent 68 is (Compound 12) 是一种抗癌剂。Anticancer agent 68 将细胞阻滞在 G2/M 期并诱导程序性细胞死亡。Anticancer agent 68 通过激活 p53 和 PTEN 诱导上调肿瘤抑制。
    Anticancer agent 68
  • HY-P10286
    Phage-derived 12/1 peptide Inhibitor
    Phage-derived 12/1 peptide 通过靶向 MDM2 和 MDMX 发挥抗肿瘤活性，从而破坏 MDM2-p53 和 MDMX-p53 相互作用，IC50 为 0.15 和 1.25 μM。
    Phage-derived 12/1 peptide
  • HY-P5910A
    Azurin p28 peptide TFA
    Azurin p28 peptide TFA 是一种可穿透肿瘤的抗肿瘤肽。Azurin p28 peptide TFA 通过形成 p28:p53 复合物减少 p53 的蛋白酶体降解。Azurin p28 peptide TFA 诱导细胞凋亡 (apoptosis) 或细胞周期停滞。Azurin p28 peptide TFA 抑制 p53 阳性肿瘤生长。Azurin p28 peptide TFA 通过抑制 VEGFR-2、FAK 和 Akt 磷酸化显示抗血管生成作用
    Azurin p28 peptide TFA
  • HY-160448
    p53 Activator 9 p53 Activator
    p53 Activator 9 (example D-4) 是 EC50 为 1.699μM 的 p53 激活剂。
    p53 Activator 9
  • HY-149988
    UNP-6457 Inhibitor
    UNP-6457 是一种有效的 MDM2-p53 相互作用抑制剂，其 IC50 值为 8.9 nM。
    UNP-6457
  • HY-163275
    MDM2-IN-24 Inhibitor
    MDM2-IN-24 (化合物 A3f) 在三阴型乳腺癌细胞中表现出 MDM2 抑制和 MDMX 激活特性，具有促细胞凋亡 (apoptosis) 和抗增殖活性。
    MDM2-IN-24
  • HY-163357
    CDK2/MDM2-IN-1 Inhibitor
    CDK2/MDM2-IN-1 (III-13) 是一种 CDK2/MDM2 双重抑制剂，对 CDK2 的 IC50 值为 2.60 nM。CDK2/MDM2-IN-1 具有抗肿瘤活性。
    CDK2/MDM2-IN-1
  • HY-146806
    YL93 Inhibitor
    YL93 是 MDM2/4 的双重抑制剂 (Ki=0.64 μM, MDM4; 1.1 nM, MDM2)。YL93 诱导细胞周期停滞和细胞凋亡 (apoptosis)。YL93 显示出 p53 依赖性的细胞生长抑制活性。
    YL93
  • HY-169412
    MAPK-IN-3
    MAPK-IN-3 (Compound 4a) 是一种抗增殖剂，对 KYSE 30，HCT 116，HGC 27 表现出特别强的抑制作用，IC50 值分别为 0.57 μM，3.27 μM 和 2.28 μM。MAPK-IN-3 通过 p53 依赖机制阻滞细胞周期，并通过 p53 非依赖机制诱导细胞凋亡，下调了细胞周期相关蛋白 (如 Cyclin D1 和 cyclin B1) 的表达，上调了促凋亡蛋白 (如裂解 PARP、裂解 caspase-7 和裂解 caspase-9)，并减少了抗凋亡蛋白 (如 Bcl-2) 的表达，增加了 KYSE 30 细胞内的 ROS 水平，并上调了与 ROS 相关的 MAPK 信号通路成员 (如 p-ERK、p-p38 和 p-JNK) 的表达。
    MAPK-IN-3
  • HY-168606A
    p53-MDM2-IN-7 hydrochloride Inhibitor
    p53-MDM2-IN-7 (compound 6d) (hydrochloride) 是 p53-MDM2 抑制剂。 p53-MDM2-IN-7 对 A549 细胞的 IC50 值是 8.13 μM。p53-MDM2-IN-7 可用于抗癌研究。
    p53-MDM2-IN-7 hydrochloride
  • HY-149024
    VEGFR-2-IN-23 p53 Activator
    VEGFR-2-IN-23 (compound 11b) 是一种有效的选择性 VEGFR-2 抑制剂，IC50 值为 0.34 nM。VEGFR-2-IN-23 显示出抗肿瘤活性。VEGFR-2-IN-23 诱导细胞凋亡 (apoptosis) 和 MCF-7 细胞停滞在 G1 期。
    VEGFR-2-IN-23
  • HY-N10502
    Colletofragarone A2 Inhibitor
    Colletofragarone A2 可从真菌 Colletotrichum sp. (13S020) 中分离获得。Colletofragarone A2 抑制 p53 突变蛋白和 HSP90，具有抗癌活性。Colletofragarone A2 能够促进 p53 突变蛋白降解和聚合，并抑制体内肿瘤生长。
    Colletofragarone A2
  • HY-146389
    Anticancer agent 50 Inducer
    Anticancer agent 50 (compound 6) 是一种有效的 ABCB1 外排泵调节剂。Anticancer agent 50 显示细胞毒作用和抗增殖作用。Anticancer agent 50 降低细胞周期蛋白 D1 的表达并诱导 p53 表达。Anticancer agent 50 具有研究T淋巴瘤的潜力。
    Anticancer agent 50
  • HY-P3508
    PNC-27
    PNC-27 是一种嵌合 p53 穿透肽，与 p53 肽样结构中的 HDM-2 结合，诱导选择性膜孔形成并导致癌细胞裂解。PNC-27 是一种抗癌肽，可用于急性髓系白血病研究。
    PNC-27
  • HY-156919
    p53 Activator 8
    p53 Activator 8 是一种 p53 激活剂。p53 Activator 8 对 MCF7 乳腺癌细胞系具有有效的抗增殖活性，IC50 值为 0.5 μM。
    p53 Activator 8
  • HY-160449
    p53 Activator 10 Activator
    p53 Activator 10 (Example C-2) 是一种靶向 p53 的 y220c 突变体的化合物。p53 Activator 10 激活参与肿瘤抑制的下游效应。
    p53 Activator 10
  • HY-133754
    MI-1063 MDM2 Inhibitor
    MI-1063 是 DMD-2 抑制剂，可阻断 MDM2-p53 相互作用，并激活 p53 的肿瘤抑制功能。MI-1063 抑制癌细胞 RS4-11 和 MV4-11 的生长，IC50 分别为 179 nM 和 93 nM。MI-1063 可用作靶蛋白配体，用于 PROTAC 降解剂 MD-265 (HY-169327) 合成。
    MI-1063
目录号 产品名 / 同用名 应用 反应物种
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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.

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