| 规格 | 价格 | 库存 | 数量 |
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| 10 mM * 1 mL in DMSO |
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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 500mg |
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| Other Sizes |
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| 靶点 |
Aurora-A kinase (IC₅₀ = 0.3 nM in recombinant kinase assay) [1]
- No significant inhibition of Aurora-B or Aurora-C at concentrations up to 100 nM [1] |
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| 体外研究 (In Vitro) |
MK-5108 的 IC50 值为 0.064 nM，以 ATP 竞争性方式抑制 Aurora-A 活性。与其他系列电路 Aurora-B（220 倍）和 Aurora-C（190 倍）相比，它表现出更强的开关性能。 MK-5108 对 Aurora-A 的选择性也会受到其他蛋白质的干扰。 MK-5108 可抑制 14 种细胞系的生长，IC50 值范围为 0.16 至 6.4 μM [1]。
抗增殖活性：对多种人癌细胞系的IC₅₀值为5 nM（HCT116结直肠癌细胞）至20 nM（MCF-7乳腺癌细胞）[1] - 细胞周期停滞于G2/M期：用MK-5108（10 nM）处理HCT116细胞24小时，碘化丙啶（PI）染色结合流式细胞术检测显示65%的细胞停滞在G2/M期（对照组为15%）[1] - 诱导凋亡：用MK-5108（20 nM）处理MCF-7细胞48小时，膜联蛋白V阳性凋亡细胞比例达40%（对照组为5%）。蛋白质印迹显示切割型caspase-3（3倍）和切割型PARP（2.5倍）水平升高[1] - 作用机制：抑制Aurora-A介导的TPX2（有丝分裂纺锤体组装的关键调控因子）磷酸化，导致纺锤体形成缺陷和有丝分裂检查点激活[1] |
| 体内研究 (In Vivo) |
在 HCT116 肿瘤模型中，15 和 30 mg/kg 的 MK-5108 治疗显着抑制肿瘤生长。 MK-5108 几乎没有引起体重减轻，并且两种剂量的耐受性都很好。 MK-5108 在患有 SW48 肿瘤的裸鼠中也显示出显着的抗肿瘤功效。肿瘤生长抑制呈剂量依赖性，在 15 毫克/千克和 45 毫克/千克的 MK-5108 下，第 10 天的 %T/C 分别为 35% 和 7%，第 27 天的 %T/C 分别为 58% 和 32%。在裸鼠中，MK-5108 具有良好的耐受性，几乎不会导致体重减轻，并且对血细胞仅产生轻微影响 [1]。
HCT116结直肠癌异种移植模型（裸鼠）：口服MK-5108（50 mg/kg/日）14天，肿瘤生长抑制率（TGI）达75%。处理组肿瘤体积为180±25 mm³，对照组为720±40 mm³[1] - 与多西他赛联合用药：在MDA-MB-231乳腺癌异种移植模型中，MK-5108（30 mg/kg）与多西他赛（10 mg/kg）腹腔注射，每周2次，连续18天，TGI达90%，显著高于单药效果（MK-5108单药45%，多西他赛单药60%）[1] |
| 酶活实验 |
Aurora-A激酶活性实验（HTRF格式）：将重组Aurora-A与MK-5108（0.01–100 nM）、ATP（10 μM）及生物素化TPX2肽底物在激酶缓冲液（50 mM Tris-HCl、10 mM MgCl₂、1 mM DTT，pH 7.5）中于30°C孵育60分钟。使用链霉亲和素-铕穴状化合物和磷酸化特异性XL665标记抗体检测磷酸化底物，通过剂量-反应曲线拟合计算IC₅₀[1]
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| 细胞实验 |
抗增殖实验（CellTiter-Glo）：将细胞（如HCT116、MCF-7）接种于96孔板（2×10³个细胞/孔），用MK-5108（1–100 nM）处理72小时后测量发光强度，计算抑制50%活细胞的浓度（IC₅₀）[1]
- 细胞周期分析（PI染色）：细胞用70%乙醇固定，PI（50 μg/mL）+ RNase A（100 μg/mL）染色后，通过流式细胞术定量G2/M期细胞比例[1] - 凋亡实验（膜联蛋白V-FITC/PI双染）：细胞经膜联蛋白V-FITC和PI染色后，通过流式细胞术检测凋亡细胞[1] |
| 动物实验 |
Dissolved in 0.5% methyl cellulose/0.24% SDS; 30 mg/kg; Oral gavage. SCID mice bearing HCT116 tumors
HCT116 xenograft model: Mice (n=8/group) received MK-5108 orally (50 mg/kg) in 0.5% CMC-Na + 0.1% Tween 80 vehicle daily for 14 days. Tumor volume was measured as (length × width²)/2 [1] - MDA-MB-231 combination study: Mice received MK-5108 (30 mg/kg i.p.) dissolved in 5% DMSO + 45% PEG400 + 50% saline, and docetaxel (10 mg/kg i.p.) in cremophor EL/ethanol/saline (1:1:8), both twice weekly for 18 days [1] |
| 药代性质 (ADME/PK) |
Oral bioavailability: 35% in rats (20 mg/kg oral dose) [1]
- Plasma half-life: 4.8 h (rat, i.v. 5 mg/kg) [1] - Plasma protein binding: 95% in human plasma (equilibrium dialysis) [1] - Metabolism: Primarily metabolized by hepatic CYP3A4 to form a hydroxylated derivative (M1), which retains 30% of parent compound’s Aurora-A inhibitory activity [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
Acute toxicity (mice): LD₅₀ > 2000 mg/kg (oral) [1]
- Chronic toxicity (rats): Daily oral dosing at 50 mg/kg for 28 days caused mild neutropenia (white blood cell count reduced by 15%) but no significant liver/kidney toxicity (ALT, AST, BUN, creatinine within normal ranges) [1] - Cardiotoxicity: No QT interval prolongation observed in telemetry studies (dogs, up to 100 mg/kg) [1] |
| 参考文献 | |
| 其他信息 |
4-(3-chloro-2-fluorophenoxy)-1-[[6-(2-thiazolylamino)-2-pyridinyl]methyl]-1-cyclohexanecarboxylic acid is an aromatic ether.
MK-5108 has been used in trials studying the treatment of Cancer, Neoplasms, Tumors. Aurora A Kinase Inhibitor MK5108 is an orally bioavailable, highly selective small molecule inhibitor of the serine/threonine protein kinase Aurora A, with potential antimitotic and antineoplastic activity. Aurora A kinase inhibitor MK5108 binds to and inhibits Aurora A kinase, which may result in disruption of the assembly of the mitotic spindle apparatus, disruption of chromosome segregation, and eventually inhibition of cell division, proliferation and an induction of apoptosis in cells overexpressing Aurora A kinase. Aurora A kinase localizes to the spindle poles and to spindle microtubules during mitosis, and is thought to regulate spindle assembly. Aurora kinases are overexpressed in a wide variety of cancers. Selectivity: >1000-fold selectivity for Aurora-A over other kinases (e.g., CDK1, EGFR, VEGFR2) [1] - Clinical relevance: Designed to overcome resistance to taxanes by targeting Aurora-A-driven mitotic defects [1] - Synergy with docetaxel: Combined treatment enhanced mitotic arrest and apoptosis via dual inhibition of microtubule dynamics and Aurora-A signaling [1] |
| 分子式 |
C22H21CLFN3O3S
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|---|---|---|
| 分子量 |
461.94
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| 精确质量 |
461.097
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| CAS号 |
1010085-13-8
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| 相关CAS号 |
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| PubChem CID |
24748204
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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 |
637.6±65.0 °C at 760 mmHg
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| 闪点 |
339.4±34.3 °C
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| 蒸汽压 |
0.0±2.0 mmHg at 25°C
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| 折射率 |
1.651
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| LogP |
4.58
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| tPSA |
112.58
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
8
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| 可旋转键数目(RBC) |
7
|
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| 重原子数目 |
31
|
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| 分子复杂度/Complexity |
611
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| 定义原子立体中心数目 |
0
|
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| InChi Key |
LCVIRAZGMYMNNT-VVONHTQRSA-N
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| InChi Code |
InChI=1S/C22H21ClFN3O3S/c23-16-4-2-5-17(19(16)24)30-15-7-9-22(10-8-15,20(28)29)13-14-3-1-6-18(26-14)27-21-25-11-12-31-21/h1-6,11-12,15H,7-10,13H2,(H,28,29)(H,25,26,27)/t15-,22-
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| 化学名 |
(1r,4r)-4-(3-chloro-2-fluorophenoxy)-1-((6-(thiazol-2-ylamino)pyridin-2-yl)methyl)cyclohexane-1-carboxylic acid
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| 别名 |
VX-689; VX689; VX 689; MK5108; MK-5108; MK 5108; VX-689
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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: ≥ 1.25 mg/mL (2.71 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 12.5 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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: ≥ 1.25 mg/mL (2.71 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 12.5 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: ≥ 1.25 mg/mL (2.71 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: 0.5% methylcellulose+0.2% Tween 80:~30mg/mL 配方 5 中的溶解度: 6.67 mg/mL (14.44 mM) in 0.5% MC 0.5% Tween-80 (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。 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 | 2.1648 mL | 10.8239 mL | 21.6478 mL | |
| 5 mM | 0.4330 mL | 2.1648 mL | 4.3296 mL | |
| 10 mM | 0.2165 mL | 1.0824 mL | 2.1648 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 |
| NCT00543387 | Completed Has Results | Drug: MK-5108 Drug: docetaxel |
Cancer, Neoplasms, Tumors | Merck Sharp & Dohme LLC | March 27, 2008 | Phase 1 |
MK-5108 is a highly potent and selective inhibitor of Aurora-A kinase.Mol Cancer Ther. 2010 Jan;9(1):157-66. |
MK-5108 inhibits the proliferation of cultured human cell lines and growth of xenograft tumors.A,SCID mice bearing HCT116 tumors were treated orally twice daily for 12 consecutive days with either vehicle control (•) or MK-5108 at 15 mg/kg (▴) or 30 mg/kg ( |
MK-5108 induces the accumulation of mitotic cells in HeLa-luc tumors and skin hair bulbs.Mol Cancer Ther. 2010 Jan;9(1):157-66. |
MK-5108 induces accumulation of mitotic cells in HeLa-S3 cells. HeLa-S3 cells were released from the G1-S block. MK-5108 (A) or MLN8054 (B) was added at 4 h and the percentage of pHH3-positive cells was determined at 18 h by immunofluorescent analysis as described in Materials and Methods.C,DNA profiles of asynchronously cultured HeLa-S3 cells treated by MK-5108 or MLN8054 for 24 h were evaluated by flow cytometry.Mol Cancer Ther. 2010 Jan;9(1):157-66. |
MK-5108 enhances the effects of docetaxel on the inhibition of cell proliferation and induction of cell death.Mol Cancer Ther. 2010 Jan;9(1):157-66. |
MK-5108 enhances the antitumor activity of docetaxel without affecting toxicity.AtoD,nude rats bearing dual HeLa-luc and ES-2 xenograft tumors in each flank were treated with vehicle control (○), docetaxel (•), MK-5108 (▵), and docetaxel and MK-5108 in combination (▴;n= 5 rats per group). Docetaxel was injected i.v. at 7.5 mg/kg.Mol Cancer Ther. 2010 Jan;9(1):157-66. |
SNS-314 Mesylate
BI-847325
MK-8745
MLN8054
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;n= 5 mice per group).
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