2. PROTAC Metabolic Enzyme/Protease
  3. Molecular Glues E1/E2/E3 Enzyme
  4. XMU-MP-8

XMU-MP-8 (SKPer1) 是一种高效的分子胶 (molecular glue) 降解剂，靶向作用于癌蛋白 SKP2。 XMU-MP-8 同时与 SKP2 的 F-box 结构域 (Kd ≈ 36 μM) 和 E3 连接酶 STUB1 的 N 端 TPR 结构域结合 (Kd ≈ 2.5 μM)，形成稳定的 SKP2-SKPer1-STUB1 三元复合物 (Kd ≈ 8.9 nM)，从而诱导 SKP2 泛素化和蛋白酶体降解。XMU-MP-8 能够选择性清除 SKP2 表达的癌细胞。XMU-MP-8 在体内表现出显著的肿瘤抑制效果和良好的安全性。XMU-MP-8 可用于非小细胞肺腺癌 (NSCLC) 和前列腺腺癌等癌症的相关研究。

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XMU-MP-8

XMU-MP-8 Chemical Structure

CAS No. : 2271314-01-1

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XMU-MP-8 相关抗体

Top Publications Citing Use of Products

  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

XMU-MP-8 (SKPer1) is a potent molecular glue degrader that targets the oncoprotein SKP2. XMU-MP-8 simultaneously binds to the F-box domain of SKP2 (Kd ≈ 36 μM) and the N-terminal TPR domain of the E3 ligase STUB1 (Kd ≈ 2.5 μM), forming a stable SKP2-SKPer1-STUB1 ternary complex (Kd ≈ 8.9 nM) that induces SKP2 ubiquitination and proteasomal degradation. XMU-MP-8 selectively eliminates SKP2-expressing cancer cells. XMU-MP-8 exhibits substantial tumour suppression with good safety profiles in vivo. XMU-MP-8 can be used for cancer research, such as non-small cell lung adenocarcinoma (NSCLC) and prostatic adenocarcinoma[1].

IC50 & Target[1]

SKP2

36 μM (Kd)

体外研究
(In Vitro)

XMU-MP-8 (10 μM，24 小时) 特异性地在 SKP2-F-C 细胞系中产生细胞存活表型，而在其他 F-C 细胞系中未观察到细胞存活，这排除了其普遍干扰 F-C 死亡蛋白激活的可能性[1]。
XMU-MP-8 (1-10 μM，0-24 小时) 可触发 SKP2 泛素化和蛋白酶体降解，显著缩短其半衰期并消耗内源性 SKP2 蛋白，但不影响其 mRNA 水平[1]。
XMU-MP-8 (72 小时) 抑制 SKP2 高表达癌细胞的增殖，其对 PC-3、A549、JHH-7、SW620、LoVo、RKO、Caco2 和 HeLa 细胞的 IC50 值分别为 3.7 μM、6.7 μM、3.7 μM、6.2 μM、4.5 μM、6.9 μM、5.6 μM 和 5.3 μM[1]。
XMU-MP-8 (10 μM，72 小时) 能完全阻断 SKP2 高表达细胞系的增殖，并诱导其大量细胞死亡[1]。
XMU-MP-8 (10 μM，24 小时) 在 SKP2 高表达细胞系 (JHH-7 和 PC-3) 中诱导 SKP2 蛋白降解和 p27 蛋白积累，而在 SKP2 低表达细胞系 (IMR-90 和 MCF-10A) 中未引起显著变化[1]。
XMU-MP-8 (2.5-10 μM，0-5 天) 对正常小鼠肠道类器官和人外周血单核细胞的生长无显著影响[1]。
XMU-MP-8 (10 μM，2.5 小时) 通过将 E3 连接酶 STUB1 募集到 SKP2 的 F-box 结构域，形成三元复合物，使 SKP2-STUB1 相互作用增强 122 倍，最终导致 SKP2 泛素化与降解[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

XMU-MP-8 相关抗体:

Western Blot Analysis[1]

Cell Line: JHH-7 and HeLa cells
Concentration: 1, 2, 5, and 10 μM
Incubation Time: 0, 2, 4, 6, 8, 12 and 24 h
Result: Reduced SKP2 levels in JHH-7 and HeLa cells in a dose- and time-dependent manner.
Degraded SKP2 through the proteasome, but not the lysosome.
Induced ubiquitination of SKP2.
Significantly reduced the SKP2 half-life of SKP2 (from 10.8 h to 3.3 h in JHH-7 cells, and from 11.3 h to 6.2 h in HeLa cells).

Western Blot Analysis[1]

Cell Line: A549 and PC-3 cells and derived genetically modified lines.
Concentration: 5 and 10 μM
Incubation Time: 2.5 and 24 h
Result: Failed to degrade SKP2-F-C when three lysine residues (3K>R) in its F-box domain were mutated.
Failed to induce ubiquitination of the SKP2 3K>R mutant protein.
Was unable to exert its anti-proliferative effect in cells where endogenous SKP2 had been replaced with the degradation-resistant 3K>R mutant.
Failed to induce SKP2 ubiquitination and degradation in STUB1 knockout cells.
Re-gained its ability to degrade SKP2 following the reconstitution of sgRNA-resistant STUB1 in STUB1 knockout cells.
Still recruited the 3K>R mutant to STUB1, even though this mutant was resistant to degradation.
体内研究
(In Vivo)

XMU-MP-8 (15 和 30 mg/kg，静脉注射，每日一次，持续 14 天) 通过降解 SKP2 在 A549 和 PC-3 异种移植小鼠模型中展现出显著的抗肿瘤功效[1]。
XMU-MP-8 (30 mg/kg，静脉注射，每日一次，持续 14 天) 在 BALB/c 裸鼠体内未表现出不良反应[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Male BALB/c nude mice (6 weeks old)[1]
Dosage: 30 mg/kg
Administration: i.v., daily for 14 days
Result: Exhibited no significant changes in body weight and liver function (ALT/AST levels).
Showed no histopathological damage in the heart, kidney, liver, lung, or spleen.
Animal Model: Male BALB/c nude mice (6 weeks old) subcutaneously injected with A549 or PC-3 cells[1]
Dosage: 15 and 30 mg/kg
Administration: i.v., daily for 14 days
Result: Completely ceased the growth of A549 tumors.
Caused a 95 % reduction in tumour growth in PC-3 xenograft model.
Caused depletion of SKP2 and an increase of p27 in the xenograft PC-3 tumour.
分子量

534.56

Formula

C26H21F3N8S
CAS 号
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
纯度 & 产品资料
参考文献

XMU-MP-8 相关分类

  • 摩尔计算器

  • 稀释计算器

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  • Do most proteins show cross-species activity?

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Keywords:

XMU-MP-82271314-01-1SKPer1SKPer 1SKPer-1Molecular GluesE1/E2/E3 EnzymeE1 activating enzymeE2 conjugating enzymeE3 ligating enzymeUbiquitin activating enzymeUbiquitin conjugating enzymeUbiquitin ligaseSKP2E3STUB1NSCLCadenocarcinomaA549PC-3SKP2-SKPer1-STUB1molecular glueInhibitorinhibitorinhibit

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