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Adavosertib (MK-1775)

Names

[ CAS No. ]:
955365-80-7

[ Name ]:
Adavosertib (MK-1775)

[Synonym ]:
2-allyl-1,8-dimethoxy-9,10-anthraquinone
3H-Pyrazolo[3,4-d]pyrimidin-3-one, 1,2-dihydro-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-2-(2-propen-1-yl)-
2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one
2-Allyl-1-[6-(2-hydroxy-2-propanyl)-2-pyridinyl]-6-{[4-(4-methyl-1-piperazinyl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one
9,10-Anthracenedione,1,8-dimethoxy-2-(2-propenyl)
2-allyl-1,8-dimethoxyanthracene-9,10-dione
MK-1775
MK1775
AZD1775

Biological Activity

[Description]:

Adavosertib (AZD-1775; MK-1775) is a potent Wee1 inhibitor with an IC50 of 5.2 nM.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Wee1
Research Areas >> Cancer

[Target]

IC50: 5.2 nM (Wee1)


[In Vitro]

Adavosertib (MK-1775) enhances the cytotoxic effects of 5-FU in p53-deficient human colon cancer cells. Adavosertib (MK-1775) inhibits CDC2 Y15 phosphorylation in cells, abrogates DNA damaged checkpoints induced by 5-FU treatment, and causes premature entry of mitosis determined by induction of Histone H3 phosphorylation[1]. Adavosertib (MK-1775) abrogates the radiation-induced G2 block in p53-defective cells but not in p53 wild-type lines[2]. The combination of gemcitabine with Adavosertib (MK-1775) produces robust anti-tumor activity and remarkably enhances tumor regression response (4.01 fold) compared to gemcitabine treatment in p53-deficient tumors[3].

[In Vivo]

In vivo, Adavosertib (MK-1775) potentiates the anti-tumor efficacy of 5-FU or its prodrug, capecitabine, at tolerable doses[1]. Adavosertib (MK-1775) (60 mg/kg twice daily, p.o.) enhances H1299 xenograft tumor response to fractionated radiotherapy[2]. Adavosertib (MK-1775) (30 mg/kg. p.o.) regresses tumor growth in PANC198, PANC215 and PANC185 as compared to GEM treated mice[3].

[Cell Assay]

Total protein is extracted from the cell pellet using a lysis solution containing 50 mM HEPES (pH 7.9), 0.4 mol/L NaCl, and 1 mM EDTA and fortified with 10 µL/mL phosphatase inhibitor cocktail 1, 10 µL/mL phosphatase inhibitor cocktail 2, 10 µL/mL protease inhibitor, and 1% NP-40. Protein concentration of the lysates is determined by the Bio-Rad protein assay. Equal amounts of protein are separated by 12% SDS-PAGE and transferred to an Immobilon membrane. Nonspecific binding sites on the membrane are blocked in 5% nonfat dry milk in Tris (20 mM)-buffered saline (150 mM, pH 7.4) with 0.1% Tween (TBS-T). Protein signals are detected by incubating the membrane in primary antibody in 5% nonfat dry milk overnight at 4°C, followed by a 45-min incubation in the appropriate peroxidase-conjugated secondary antibody. The membrane is then developed by enhanced chemiluminescence with ECL plus Western Blotting Detection Reagents on a Typhoon 9400 scanner.

[Animal admin]

Tumor xenografts are produced in the leg by im inoculation of 1×106 Calu-6 cells in 10 µL. Irradiation and Adavosertib (MK-1775) treatment are started when tumors reach 8 mm diameter and continue for 5 days. Gamma-rays are delivered locally to the tumor-bearing legs of unanesthetized mice using a small-animal irradiator consisting of two parallel-opposed 137Cs sources, at a dose rate of 5 Gy/min. Tumors are irradiated twice daily separated by 6 h. Adavosertib (MK-1775) is given by gavage in 0.1 mL volumes 1 h before and 2 h after the first daily radiation dose.

[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;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. Epub 2011 Jul 28.

[3]. 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. Epub 2011 Mar 9.


[Related Small Molecules]

PD0166285

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
723.8±70.0 °C at 760 mmHg

[ Molecular Formula ]:
C27H32N8O2

[ Molecular Weight ]:
500.595

[ Flash Point ]:
391.5±35.7 °C

[ Exact Mass ]:
500.264832

[ PSA ]:
104.34000

[ LogP ]:
0.50

[ Vapour Pressure ]:
0.0±2.5 mmHg at 25°C

[ Index of Refraction ]:
1.655

Safety Information

[ Hazard Codes ]:
Xi

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds