MMRi62 是一种铁死亡 (ferroptosis) 诱导剂，靶向MDM2-MDM4(抑癌基因 p53 负调控因子)。MMRi62 对胰腺导管腺癌 (PDAC) 细胞显示出 p53 独立的促凋亡 (apoptosis) 活性，并诱导其自噬 (autophagy)。MMRi62 诱导铁死亡，伴随着活性氧增加和铁蛋白重链 (FTH1) 溶酶体降解。MMRi62 还可导致突变型 p53 的蛋白酶体降解，并对具有 KRAS 和 TP53 高频突变特征的原位异种移植 PDAC 小鼠模型具有体内药效。
| 生物活性 | MMRi62, aferroptosisinducer targetingMDM2-MDM4(negative regulators of tumor suppressor p53). MMRi62 shows a P53-independent pro-apoptotic activity against pancreatic ductal adenocarcinoma (PDAC) cells and induceautophagy. 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[1][2]. |
体外研究
(In Vitro) | MMRi62 通过诱导细胞死亡抑制胰腺导管腺癌细胞 (PDAC) 的增殖、克隆和球形生长[1]。
MMRi62 (3 nM-100 μM; 4 h) 与 MDM2 和 MDM4 的环环异质二聚体结合，Kd值为 1.39 μM[2]。
MMRi62 (10 nM-1 μM; 72 h) 诱导白血病细胞凋亡，抑制白血病细胞的 IC50分别为 0.34 μM (HL60) 和 0.22 μM (HL60VR)[2]。
MMRi62 (5 μM, 10μM; 24 h) 以剂量依赖性的方式降低 MDM2B 自泛素化，增加 MDM4 泛素化[2].
MMRi62 是 E3 连接酶修饰剂，能够将底物偏好从 MDM2 切换到 MDM4[2]。
MMRi62 (5 μM; 24, 72 h) 诱导细胞凋亡，不依赖于 p53[2]。
Western Blot Analysis[2] | Cell Line: | WT-p53 bearing MV4-11 cells; 293cells transfected with MDM2B and MDM4 | | Concentration: | 2, 2.5, 5, 10, 40, 80, 160 μM | | Incubation Time: | 24 hours | | Result: | Increased cleaved PARP protein and activatedcaspase 3 level in wt-p53 bearing MV4-11 cells at 2 μM for 24 h.
Decreased MDM2B autoubiquitination, increasedMDM4 ubiquitination at 5 μM and 10 μM for 24 h.
Induced MDM2-dependent degradation of MDM4protein at 5 μM in NALM6 cells. |
Cell Proliferation Assay[2] | Cell Line: | Primary AML patient cells, NALM6cells and NALM6shp53 cells | | Concentration: | 1, 10, 25, and 50 μM | | Incubation Time: | 24 hours and 72 hours | | Result: | Induced NALM6 cells apoptosis at 24 hand induced Primary AML patient cells at 72 h. |
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体内研究
(In Vivo) | MMRi62 在原位异种移植 PDAC 小鼠模型中显示出抗肿瘤活性，通过抑制 NCOA4 和突变型 p53 下调，抑制小鼠的肿瘤生长[1]。
MMRi62 也完全消除原位肿瘤的转移[1]。
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, protect from light *In solvent : -80°C, 6 months; -20°C, 1 month (protect from light) |
| 溶解性数据 | In Vitro: DMSO : 62.5 mg/mL(157.72 mM;ultrasonic and warming and heat to 60℃) 配制储备液 | 1 mM | 2.5235 mL | 12.6177 mL | 25.2353 mL | | 5 mM | 0.5047 mL | 2.5235 mL | 5.0471 mL | | 10 mM | 0.2524 mL | 1.2618 mL | 2.5235 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month (protect from light)。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 |
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