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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.

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MK-1775 Chemische Struktur

Cas No.: 955365-80-7

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10mM (in 1mL DMSO)
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5mg
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10mg
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Sample solution is provided at 25 µL, 10mM.

Description of MK-1775

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.

Protocol of MK-1775

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:
[1]. 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.
[2]. Rajeshkumar NV, et al. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011 May 1;17(9):2799-806.

Chemical Properties of MK-1775

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.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table of MK-1775

Prepare stock solution
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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