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.

目录号 产品名 作用方式 纯度
  • HY-10029
    Nutlin-3a MDM2 Inhibitor 98.07%
    Nutlin-3a (Rebemadlin) 是 Nutlin-3 的活性对映体,是一种有效的 MDM2 抑制剂。Nutlin-3a 可抑制 MDM2-p53 相互作用,稳定 p53 蛋白,从而诱导细胞自噬 (autophagy) 和凋亡 (apoptosis)。Nutlin-3a 有潜力用于 TP53 野生型卵巢癌的研究。
  • HY-17412
    Minocycline hydrochloride

    盐酸米诺环素

    p53 Activator 99.79%
    Minocycline hydrochloride 是一种口服有效、能透过血脑屏障的半合成四环素类抗生素。Minocycline hydrochloride 是一种缺氧诱导因子 (HIF-1α) 抑制剂。Minocycline hydrochloride 具有抗癌(anti-cancer),抗炎(anti-inflammatory) 和谷氨酸 (glutamate) 拮抗作用。Minocycline hydrochloride 降低谷氨酸神经传递,显示神经保护特性和抗抑郁作用。Minocycline hydrochloride 通过与细菌核糖体30S亚基结合,抑制细菌蛋白的合成,从而产生抑菌 (bacteriostatic) 作用。
  • 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-15484
    Pifithrin-α hydrobromide p53 Inhibitor 98.05%
    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-12296
    Navtemadlin MDM2 Inhibitor 99.43%
    Navtemadlin (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-103640
    Amifostine thiol dihydrochloride

    氨磷汀杂质2

    p53 Activator ≥98.0%
    Amifostine thiol (WR-1065) dihydrochloride 可以保护正常组织免受某些癌症药物的毒性作用,并通过 JNK 依赖性信号通路激活 p53
  • HY-16271
    Kevetrin hydrochloride p53 Activator ≥98.0%
    Kevetrin hydrochloride 是一种有效的 p53 激活剂,可诱导 TP53 野生型和突变型急性髓系白血病细胞凋亡。Kevetrin 对原始胚细胞具有优先的细胞毒性。
  • HY-108639
    MIRA-1 p53 Activator 99.76%
    MIRA-1 是一种马来酰亚胺类似物。MIRA-1 可通过恢复 p53 依赖的转录转激活诱导 p53 突变细胞凋亡 (apoptosis)。MIRA-1 具有抗肿瘤活性。
  • HY-50696
    Nutlin-3 MDM2 Inhibitor 99.18%
    Nutlin-3 是一种有效的 p53-MDM2 抑制剂,Ki 为 90 nM。
  • HY-19980
    Eprenetapopt p53 Activator ≥99.0%
    Eprenetapopt (APR-246) 是首创的在 TP53 突变细胞中恢复野生型p53功能的小分子。Eprenetapopt 引发肿瘤细胞凋亡。Eprenetapopt 还抑制硒蛋白硫氧还蛋白还原酶 1 (TrxR1)。
  • 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-18935A
    CBL0137 hydrochloride p53 Activator 99.66%
    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-18658
    Siremadlin MDM2 Inhibitor 99.82%
    Siremadlin (NVP-HDM201) 是口服有效的选择性 p53-MDM2 抑制剂。
  • HY-123076
    Pifithrin-α, p-Nitro, Cyclic p53 Inhibitor ≥99.0%
    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-114312
    MD-224 MDM2 Inhibitor 98.08%
    MD-224 是基于蛋白水解定位嵌合体 (PROTAC) 的高效小分子 (MDM2) 降解物。MD-224 由 CereblonMDM2配体组成。MD-224 在人白血病细胞中,诱导 MDM2 的快速降解 (<1 nM),抑制 RS4;11 细胞生长的 IC50 值为 1.5 nM。MD-224 有可能成为一类新的抗癌剂。
  • HY-B0639
    Amifostine

    氨磷汀

    p53 Activator ≥98.0%
    Amifostine (WR2721) 是一种广谱细胞保护剂和辐射防护剂。Amifostine 可选择性保护正常组织免受放射线和化学疗法造成的损害。Amifostine 是有效的 HIF-α1p53 诱导剂。Amifostine 通过清除氧衍生的自由基来保护细胞免受损伤。Amifostine 可降低肾脏毒性并具有抗血管生成作用。
  • HY-101266
    Milademetan MDM2 Inhibitor 98.77%
    Milademetan (DS-3032) 是特异性的、具有口服活性的 MDM2 抑制剂,用于急性髓系白血病和实体肿瘤的研究。Milademetan (DS-3032) 可诱导 G1 细胞周期阻滞、衰老和凋亡。
  • HY-101518
    Alrizomadlin MDM2 Inhibitor 98.16%
    Alrizomadlin (APG-115) 是一种口服活性小分子 MDM2 蛋白抑制剂, 可与 MDM2 蛋白结合,IC50 值和 Ki 值分别为3.8 nM 和 1 nM。Alrizomadlin 可阻断 MDM2 与 p53 的相互作用并且以 p53 依赖性方式诱导细胞周期停滞和凋亡 (apoptosis)。
  • HY-112780
    UC2288 Inhibitor 99.92%
    UC2288 是一种新型的、具有细胞通透性和口服活性的 p21 衰减试剂 (对 p21 具有相对选择性活性),基于索拉非尼 (HY-10201) 的结构合成。UC2288 在不依赖 p53 的情况下下调 p21 mRNA 的表达,降低 p21 蛋白水平,对 p21 蛋白的稳定性影响很小。UC2288 对VEGFR2 和 Raf 激酶没有抑制作用,即使在 10 μM。
  • HY-10940
    Pifithrin-μ p53 Inhibitor 99.53%
    Pifithrin-μ 是一种 p53HSP70 的抑制剂,具有抗肿瘤和神经保护作用。

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.