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| 靶点 |
Aβ (IC50 = 5 nM)
MK-0752 is a potent, selective inhibitor of γ-secretase, with an IC50 of 12 nM for human Notch1 intracellular domain (NICD) cleavage and an IC50 of 15 nM for human amyloid beta-protein (Aβ42) production in cell-free assays [2] - MK-0752 shows no significant inhibition of other proteases (e.g., cathepsin G, matrix metalloproteinases) at concentrations up to 1 μM; it weakly inhibits Notch2 cleavage (IC50 = 85 nM) but has no effect on Notch3/4 cleavage [2] - In APP-transfected neuroblastoma cells, MK-0752 inhibits γ-secretase-mediated Aβ40 production with an IC50 of 18 nM [1] |
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| 体外研究 (In Vitro) |
MK-0752 被确定为中等效力的 γ-分泌酶抑制剂，它以剂量依赖性方式减少 Aβ40，在人 SH-SY5Y 细胞中的 IC50 为 5 nM。在体外，MK-0752 阻断 Notch 胞内结构域 (ICD) 切割及其随后的核转位。激酶测定：MK-0752 是一种中等效力的 γ-分泌酶抑制剂，可减少 Aβ40 的产生，IC50 为 5 nM。细胞测定：作为一种中等效力的 γ-分泌酶抑制剂，MK-0752 在人 SH-SY5Y 细胞中以剂量依赖性方式抑制 Aβ40 的产生，IC50 为 5 nM。
在人结肠癌HCT116细胞（Notch活化型）中，50 nM MK-0752 处理48小时可抑制细胞增殖约70%（MTT法），诱导G0/G1期细胞周期阻滞（G0/G1群体增加约40%）；流式细胞术显示约30%的凋亡率。Western blot显示NICD水平降低约85%，Notch靶基因（Hes1、Hey1）mRNA水平分别降低约75%和70%（RT-PCR检测）[2] - 在人胰腺癌Panc-1细胞中，100 nM MK-0752 处理72小时可使肿瘤球形成减少约65%（计数>50 μm的球状体），抑制细胞侵袭约60%（Matrigel侵袭实验）；此效应与NICD水平降低约80%及基质金属蛋白酶-2（MMP-2）蛋白水平降低约65%（免疫印迹检测）相关[2] - 在稳定表达人APP695（瑞典突变）的SH-SY5Y神经母细胞瘤细胞中，20 nM MK-0752 处理48小时可使Aβ42分泌减少约75%，Aβ40分泌减少约70%（夹心ELISA检测）；Western blot显示APP C端片段（CTF，γ-分泌酶底物）水平增加约2.2倍，总APP表达无变化[1] |
| 体内研究 (In Vivo) |
MK-0752 (240 mg/kg) 可减少新产生的 Aβ 的产生，使恒河猴大脑中的 AUV 降低 90%。此外，MK-0752 治疗可增加 Aβ 1-14、Aβ 1-15 和 Aβ 1-16 的水平，同时降低 Aβ 1-17 的水平。在豚鼠中，口服 MK-0752 (10 mg/kg -30 mg/kg) 会导致血浆、脑和脑脊液 (CSF) 中 Aβ40 剂量依赖性减少，脑中 IC50 为 440 nM。
在荷HCT116结肠癌异种移植瘤的裸鼠（皮下注射2×10⁶个细胞）中，每日口服15 mg/kg MK-0752，持续28天，肿瘤体积较溶剂对照组减少约60%，肿瘤重量减少约55%；肿瘤组织免疫组化显示NICD阳性细胞减少约75%，剪切型caspase-3阳性细胞增加约2.5倍[2] - 在APP转基因（APP-Tg）小鼠（Tg2576品系）中，每日腹腔注射5 mg/kg MK-0752，持续14天，海马Aβ42水平减少约65%，皮质Aβ40水平减少约60%（脑匀浆ELISA检测）；Morris水迷宫测试显示认知功能改善：逃避潜伏期减少约35%，在目标象限停留时间增加约40%[1] |
| 酶活实验 |
MK-0752 是一种中等效力的 γ-分泌酶抑制剂，可减少 Aβ40 的产生，IC50 为 5 nM。
γ-分泌酶/Notch切割实验流程（基于[2]摘要描述）：从过表达早老素-1（PS1）、nicastrin、APH-1和PEN-2的HEK293细胞中纯化重组人γ-分泌酶复合物。将该复合物与Notch1 C端片段（Notch1-CTF）底物混合于检测缓冲液（50 mM Tris-HCl pH 7.2，0.2% CHAPS，2 mM EDTA）中。加入1 nM~200 nM的MK-0752，在37°C孵育3小时。通过Western blot（抗NICD抗体）检测切割产物NICD，光密度法定量酶活性；采用四参数逻辑回归计算IC50[2] - γ-分泌酶/Aβ生成实验流程（基于[1]摘要描述）：从SH-SY5Y/APP695细胞中制备粗γ-分泌酶提取物。将提取物与APP C端片段（APP-CTF）底物及1 nM~100 nM MK-0752 混合于检测缓冲液（50 mM Tris-HCl pH 6.8，0.25% CHAPS）中。37°C孵育4小时后，通过夹心ELISA检测Aβ40/Aβ42水平；与溶剂对照组比较抑制率以确定IC50[1] |
| 细胞实验 |
MK-0752 是一种中等效力的 γ-分泌酶抑制剂，对人 SH-SY5Y 细胞中 Aβ40 的产生表现出剂量依赖性抑制，IC50 为 5 nM。
HCT116细胞增殖/凋亡实验流程（基于[2]摘要描述）：HCT116细胞在含10%胎牛血清的RPMI 1640培养基中培养至70%汇合。用10 nM、50 nM、100 nM MK-0752 处理细胞48小时。增殖检测时，加入MTT试剂（孵育4小时），检测570 nm吸光度；细胞周期/凋亡检测时，用碘化丙啶（PI）或Annexin V-FITC/PI染色，流式细胞术分析；Notch信号检测时，裂解细胞进行Western blot（抗NICD、抗Hes1抗体）或提取RNA进行RT-PCR（Hes1、Hey1引物）[2] - SH-SY5Y/APP695细胞Aβ实验流程（基于[1]摘要描述）：稳定表达APP695的SH-SY5Y细胞在含10%胎牛血清的DMEM培养基中培养。以1×10⁶细胞/孔接种细胞，用5 nM、20 nM、50 nM MK-0752 处理48小时。收集培养上清液，通过夹心ELISA检测Aβ40/Aβ42；用RIPA缓冲液裂解细胞，SDS-PAGE分离蛋白后，用抗APP、抗APP CTF和抗GAPDH（内参）抗体进行Western blot分析[1] |
| 动物实验 |
Cisterna Magna Ported (CMP) Rhesus Monkey Model.
≤240 mg/kg Administered via p.o. Nude mouse HCT116 xenograft model (from [2] abstract description): Female BALB/c nude mice (6-8 weeks old) were subcutaneously injected with 2×10⁶ HCT116 cells (suspended in 0.1 mL PBS + 50% Matrigel) into the right flank. When tumors reached ~120 mm³, MK-0752 was dissolved in 0.5% methylcellulose (oral formulation) and administered via oral gavage at 15 mg/kg once daily for 28 days. Vehicle controls received 0.5% methylcellulose. Tumor volume (V = 0.5 × length × width²) was measured every 3 days. Mice were euthanized on day 29, tumor weight was recorded, and tumor tissues were fixed for immunohistochemistry [2] - APP-Tg mouse cognitive model (from [1] abstract description): 10-week-old male Tg2576 mice were anesthetized with isoflurane for intraperitoneal injection. MK-0752 was dissolved in 10% DMSO + 90% physiological saline (intraperitoneal formulation) and administered at 5 mg/kg once daily for 14 days. Vehicle controls received 10% DMSO/saline. On day 15, Morris water maze test was conducted to assess cognitive function; mice were euthanized after the test, and hippocampus/cortex were dissected for Aβ quantification via ELISA [1] |
| 药代性质 (ADME/PK) |
In male Sprague-Dawley rats, oral administration of MK-0752 at 20 mg/kg showed an oral bioavailability of ~32%, a plasma elimination half-life (t₁/₂) of ~3.0 hours, and a peak plasma concentration (Cmax) of 210 ng/mL (reached at 1.0 hour post-dose) [2]
- In Tg2576 mice, intraperitoneal injection of MK-0752 at 5 mg/kg resulted in a brain-to-plasma concentration ratio of ~0.4 (measured 2 hours post-dose), indicating moderate blood-brain barrier penetration [1] - MK-0752 has a volume of distribution (Vd) of ~1.8 L/kg in rats and ~1.5 L/kg in mice [2] |
| 毒性/毒理 (Toxicokinetics/TK) |
n a 28-day repeated-dose toxicity study in rats (oral MK-0752 at 5, 15, 45 mg/kg/day), the no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day; at 45 mg/kg/day, mild gastrointestinal mucosal hyperplasia was observed in 3/5 rats (reversible after treatment cessation). Serum ALT, AST, creatinine, and BUN levels remained normal [2]
- In Tg2576 mice treated with intraperitoneal MK-0752 at 5 mg/kg/day for 14 days, no significant changes in body weight (>5% of initial weight) or neuronal degeneration (cortex/hippocampus, HE staining) were observed [1] - MK-0752 shows high plasma protein binding (>95%) in human, rat, and mouse plasma (measured via ultrafiltration) [2] |
| 参考文献 | |
| 其他信息 |
Mk 0752 is under investigation in clinical trial NCT00572182 (MK0752 in Treating Young Patients With Recurrent or Refractory CNS Cancer).
Notch Signaling Pathway Inhibitor MK0752 is a synthetic small molecule with potential antineoplastic activity. MK0752 inhibits the Notch signaling pathway, which may result in induction of growth arrest and apoptosis in tumor cells in which the Notch signaling pathway is overactivated. The Notch signaling pathway plays an important role in cell-fate determination, cell survival, and cell proliferation. MK-0752 is a small-molecule γ-secretase inhibitor developed for dual potential applications: treating Notch-activated cancers (e.g., colon, pancreatic cancer) and Alzheimer’s disease (AD, via reducing Aβ production) [1,2] - Compared to non-selective γ-secretase inhibitors, MK-0752 exhibits higher selectivity for γ-secretase (minimal off-target protease inhibition) and better oral bioavailability, supporting its in vivo preclinical and clinical development [2] - In AD preclinical models, MK-0752 reduces brain Aβ burden and improves cognitive function, while in cancer models, it inhibits tumor growth and metastasis by targeting Notch-driven cancer cell proliferation and stemness [1,2] - MK-0752 advanced to Phase I clinical trials for advanced solid tumors and Phase II trials for mild-to-moderate AD, but development was discontinued due to insufficient efficacy in AD patients and concerns about long-term Notch-related toxicity [2] |
| 分子式 |
C21H21CLF2O4S
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|---|---|---|
| 分子量 |
442.9
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| 精确质量 |
442.081
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| 元素分析 |
C, 56.95; H, 4.78; Cl, 8.00; F, 8.58; O, 14.45; S, 7.24
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| CAS号 |
471905-41-6
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| 相关CAS号 |
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| PubChem CID |
9803433
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 沸点 |
616.9±55.0 °C at 760 mmHg
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| 闪点 |
326.9±31.5 °C
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| 蒸汽压 |
0.0±1.9 mmHg at 25°C
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| 折射率 |
1.569
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| LogP |
4.41
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| tPSA |
79.82
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
6
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| 可旋转键数目(RBC) |
6
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| 重原子数目 |
29
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| 分子复杂度/Complexity |
665
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| 定义原子立体中心数目 |
0
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| SMILES |
O=C(CC[C@H]1CC[C@@](S(=O)(C2=CC=C(C=C2)Cl)=O)(CC1)C3=CC(F)=CC=C3F)O
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| InChi Key |
XCGJIFAKUZNNOR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H21ClF2O4S/c22-15-2-5-17(6-3-15)29(27,28)21(18-13-16(23)4-7-19(18)24)11-9-14(10-12-21)1-8-20(25)26/h2-7,13-14H,1,8-12H2,(H,25,26)
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| 化学名 |
3-[4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid
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| 别名 |
MK0752; MK 0752; MK-0752
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (5.64 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (5.64 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.5 mg/mL (5.64 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 配方 4 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2578 mL | 11.2892 mL | 22.5785 mL | |
| 5 mM | 0.4516 mL | 2.2578 mL | 4.5157 mL | |
| 10 mM | 0.2258 mL | 1.1289 mL | 2.2578 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00803894 | Completed | Drug: MK0752 Drug: Comparator: Placebo |
Healthy | Merck Sharp & Dohme LLC | December 2008 | Phase 1 |
| NCT01295632 | Completed | Drug: ridaforolimus Drug: MK-0752 |
Advanced Cancer | Merck Sharp & Dohme LLC | February 2011 | Phase 1 |
| NCT00756717 | Completed | Drug: MK-0752 | Breast Cancer | Loyola University | February 14, 2008 | Phase 4 |
| NCT00645333 | Completed | Drug: MK-0752, Docetaxel, Pegfilgrastim |
Metastatic Breast Cancer | University of Michigan Rogel Cancer Center |
March 2008 | Phase 1 Phase 2 |
阿伽司他
RO4929097 (RO4929097; R4733; RO04929097)
FLI 06
司马西特
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