MK-1775 (Synonyms: MK1775,MK 1775) |
Katalog-Nr.GC16030 |
MK-1775 ist ein potenter und selektiver Inhibitor der Wee1-Kinase mit einem IC50-Wert von 5,2 nM.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 955365-80-7
Sample solution is provided at 25 µL, 10mM.
MK-1775 ist ein potenter und selektiver Inhibitor der Wee1-Kinase mit einem IC50-Wert von 5,2 nM. MK-1775 ist 2- bis 3-mal weniger potent gegen Yes mit einem IC50-Wert von 14 nM.[1].
In In-vitro-Wirksamkeitstests zeigte sich, dass MK-1775 die Phosphorylierung von CDC2 an Tyr15 mit einem EC50-Wert von 85 nM in mit Gemcitabin vorbehandelten Zellen hemmte. Die Behandlung mit MK-1775 induzierte pHH3 dosisabhängig mit einem EC50-Wert von 81 nM.[1] In In-vitro-Wirksamkeitstests wurde gezeigt, dass die Behandlung mit 10 nM Panobinostat in Kombination mit 250 nM oder 500 nM MK-1775 in U937-Zellen zu Kombinationsindexwerten (CI) von 0,95 und 0,73 führte, während U937-Zellen, die mit 20 nM Panobinostat in Kombination mit 250 nM oder 500 nM MK-1775 behandelt wurden, CI-Werte von 0,39 bzw. 0,40 aufwiesen.[3] In vitro führte die Behandlung mit 0,1, 0,3, 1 μM MK-1775 für 48 Stunden in LSCC-Zellen sowie in TU212- und KB-3-1-Zellen dosisabhängig zu früher Apoptose (Annexin V+/PI-) und später Apoptose (Annexin V+/PI+). Darüber hinaus erhöhte die MK-1775-Behandlung dosisabhängig die Proteinspiegel des Apoptosemarkers gespaltenes PARP.[5]
In vivo verstärkte die orale Behandlung mit 60 mg/kg MK-1775 die Reaktion von H1299-Xenograft-Tumoren auf fraktionierte Strahlentherapie bei nackten Mäusen.[2] In einem In-vivo-Experiment wurde gezeigt, dass die Behandlung mit entweder MK-1775 (20 mg/kg) oder Panobinostat (10 mg/kg) allein bei Mäusen mit BxPC-3-Xenograft-Tumoren zu einer mäßigen Verzögerung des äußerlich messbaren Tumorwachstums führte (30,9% bzw. 37,8% am Tag 20). Die Kombination von MK-1775 (20 mg/kg) mit Panobinostat (10 mg/kg) führte jedoch zu einer deutlichen Verzögerung des Tumorwachstums mit 58,7% Tumorwachstumshemmung am Tag 20.[4] In vivo wurden nackte Mäuse mit 50 mg/kg oralem MK-1775 behandelt, wobei MK-1775 das Wachstum von KB-3-1-Xenografts mit einer Hemmungsrate von 30,04% durch Reduktion des Tumorvolumens und -gewichts hemmte. Zudem kann MK-1775 bei der angegebenen Dosis Toxizität bei Mäusen verursachen.[6]
References:
[1]Hirai H, et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010 Apr 1;9(7):514-22.
[2]Bridges KA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011 Sep 1;17(17):5638-48.
[3]Qi W, et al. Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. Cancer Biol Ther. 2015;16(12):1784-93.
[4]Wang G, et al. Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer. Cancer Lett. 2015 Jan 28;356(2 Pt B):656-68.
[5]Yuan ML, et al Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma. Front Pharmacol. 2018 Sep 28;9:1041.
[6]Yuan ML, et al. Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma. Front Pharmacol. 2018 Sep 28;9:1041.
Cell experiment [1]: | |
Cell lines | H1299 cells |
Preparation Method | H1299 cells were treated for 1 h with 200 nM MK-1775, irradiated with 7.5 Gy, incubated for an additional 18 h in MK-1775, and harvested for assessment of apoptosis at 24, 48, and 72 h post-irradiation. |
Reaction Conditions | 200 nM, 1 h |
Applications | The dose of 7.5 Gy induced levels of apoptosis of only about 5% above control at any time point and these levels of apoptosis were not significantly enhanced by MK-1775. |
Animal experiment [2]: | |
Animal models | 6-week-old female nu/nu athymic mice |
Preparation Method | When tumors reached a volume of ~200 mm3, mice were individually identified and randomly assigned to treatment groups, with 5–6 mice (8–10 evaluable tumors) in each group: 1) control; 2) MK-1775 (30 mg/kg. p.o., once daily for 4 weeks; 3) GEM (100 mg/kg, i.p., twice weekly on days 1 and 4) for 4 weeks; 4) GEM followed 24 h later by MK-1775 in the above mentioned dose. |
Dosage form | 30 mg/kg. p.o., |
Applications | Single agent MK-1775 treatment produced greater than 50% inhibition of tumor growth in two xenografts (PANC286 and PANC198). |
References: |
Cas No. | 955365-80-7 | SDF | |
Überlieferungen | MK1775,MK 1775 | ||
Chemical Name | 1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one | ||
Canonical SMILES | CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O | ||
Formula | C27H32N8O2 | M.Wt | 500.6 |
Löslichkeit | ≥ 25.03mg/mL in DMSO | Storage | Store at -20°C |
General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. |
Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
1 mM | 1.9976 mL | 9.988 mL | 19.976 mL |
5 mM | 0.3995 mL | 1.9976 mL | 3.9952 mL |
10 mM | 0.1998 mL | 0.9988 mL | 1.9976 mL |
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