MK-1775Wee1 kinase inhibtor,potent and ATP-competitive CAS# 955365-80-7 |
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| Cas No. | 955365-80-7 | SDF | Download SDF |
| PubChem ID | 24856436 | Appearance | Powder |
| Formula | C27H32N8O2 | M.Wt | 500.6 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | AZD1775; Adavosertib | ||
| Solubility | DMSO : 125 mg/mL (249.70 mM; Need ultrasonic) | ||
| 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 | ||
| SMILES | CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O | ||
| Standard InChIKey | BKWJAKQVGHWELA-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C27H32N8O2/c1-5-13-34-25(36)21-18-28-26(29-19-9-11-20(12-10-19)33-16-14-32(4)15-17-33)31-24(21)35(34)23-8-6-7-22(30-23)27(2,3)37/h5-12,18,37H,1,13-17H2,2-4H3,(H,28,29,31) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | MK-1775 is a potent and selective inhibitor of Wee1 with IC50 of 5.2 nM. | |||||
| Targets | Wee1 | |||||
| IC50 | 5.2 nM | |||||
MK-1775 Dilution Calculator
MK-1775 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.9976 mL | 9.988 mL | 19.976 mL | 39.9521 mL | 49.9401 mL |
| 5 mM | 0.3995 mL | 1.9976 mL | 3.9952 mL | 7.9904 mL | 9.988 mL |
| 10 mM | 0.1998 mL | 0.9988 mL | 1.9976 mL | 3.9952 mL | 4.994 mL |
| 50 mM | 0.04 mL | 0.1998 mL | 0.3995 mL | 0.799 mL | 0.9988 mL |
| 100 mM | 0.02 mL | 0.0999 mL | 0.1998 mL | 0.3995 mL | 0.4994 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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MK-1775 is a potent and selective small molecule inhibitor of Wee1 kinase, with an IC50 value of 5.2 nM in in vitro kinase assays. It functions as a Wee1 inhibitor in an ATP-competitive manner [1].
Previous research has shown that MK-1775 inhibited Wee1 activity and abrogated the DNA damage checkpoint usually in p53-deficient cells. It sensitized p53-inactivated tumor cells to various antitumor agents, including gemcitabine, carboplatin, cisplatin and radiation in both in vitro and in vivo settings. Moreover, only sequential treatment with the DNA-damaging agent followed by MK-1775 increased cytotoxic effects of these antitumor agents and enhanced cell death induction [1]. MK-1775 also inhibited Cdc2 Y15 phosphorylation in cells, but MK-1775 monotherapy did not induce tumor regression in some cases. Hence, a combination of DNA-damaging agents with MK-1775 is usually offered to produce dramatic antitumor activity [1]. A recent study demonstrated that heterogeneous distribution to brain tumors can limit the efficacy of MK-1775 combined with temozolomide in glioblastoma multiforme [2].
Meanwhile, MK-1775 also acts as a single antitumor agent for inducing apoptosis in sarcoma cells. The cytotoxic effect of MK-1775 on sarcoma cells seems to be independent of p53 status [3]. Another research showed that MK-1775 could also induce DNA damage without additional chemotherapy or radiation in S-phase cells. PKMYT1, a kinase functionally related to Wee1, might serve as an enrichment biomarker for MK-1775 sensitivity. Depletion of PKMYT1 decreases the EC(50) of MK-1775 by five-fold but has no effect on the sensitivity of other cytotoxic drugs. In addition, depletion of PKMYT1 promotes the DNA damage by MK-1775 [4].
References:
Hirai H, Iwasawa Y, Okada M et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009 Nov;8(11):2992-3000.
Pokorny JL, Calligaris D, Gupta SK et al. The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma. Clin Cancer Res. 2015 Apr 15;21(8):1916-24.
3. Kreahling JM, Gemmer JY, Reed D et al. MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther. 2012 Jan;11(1):174-82.
4. Guertin AD, Li J, Liu Y et al. Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther. 2013 Aug;12(8):1442-52.
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Targeting of Carbon Ion-Induced G2 Checkpoint Activation in Lung Cancer Cells Using Wee-1 Inhibitor MK-1775.[Pubmed:26645158]
Radiat Res. 2015 Dec;184(6):660-9.
The potent inhibitor of the cell cycle checkpoint regulatory factor Wee-1, MK-1775, has been reported to enhance non-small cell lung cancer (NSCLC) cell sensitivity to photon radiation by abrogating radiation-induced G2 arrest. However, little is known about the effects of this sensitizer after exposure to carbon (C)-ion radiation. The purpose of this study was therefore to investigate the effects of C ions in combination with MK-1775 on the killing of NSCLC cells. Human NSCLC H1299 cells were exposed to X rays or C ions (290 MeV/n, 50 keV/mum at the center of a 6 cm spread-out Bragg peak) in the presence of MK-1775. The cell cycle was analyzed using flow cytometry and Western blotting. Radiosensitivity was determined using clonogenic survival assays. The mechanisms underlying MK-1775 radiosensitization were studied by observing H2AX phosphorylation and mitotic catastrophe. G2 checkpoint arrest was enhanced 2.3-fold by C-ion exposure compared with X-ray exposure. Radiation-induced G2 checkpoint arrest was abrogated by MK-1775. Exposure to radiation resulted in a significant reduction in the mitotic ratio and increased phosphorylation of cyclin-dependent kinase 1 (Cdk1), the primary downstream mediator of Wee-1-induced G2 arrest. The Wee-1 inhibitor, MK-1775 restored the mitotic ratio and suppressed Cdk1 phosphorylation. In addition, MK-1775 increased H1299 cell sensitivity to C ions and X rays independent of TP53 status. MK-1775 also significantly increased H2AX phosphorylation and mitotic catastrophe in irradiated cells. These results suggest that the G2 checkpoint inhibitor MK-1775 can enhance the sensitivity of human NSCLC cells to C ions as well as X rays.
Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo.[Pubmed:26529495]
Cancer Biol Ther. 2015;16(12):1784-93.
MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.
Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors.[Pubmed:25964244]
J Clin Oncol. 2015 Oct 20;33(30):3409-15.
PURPOSE: Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (gammaH2AX) levels in paired tumor biopsies. PATIENTS AND METHODS: AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and gammaH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD. RESULTS: Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in gammaH2AX levels (three of five paired biopsies) were demonstrated. CONCLUSION: This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies.
HPLC-UV method for simultaneous determination of MK-1775 and AZD-7762 in both acetonitrile-aqueous solution and mouse plasma.[Pubmed:28088043]
J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Feb 15;1044-1045:70-76.
A sensitive and precise method is described for the simultaneous determination of two small molecule kinase inhibitors: MK-1775 (MK) and AZD-7762 (AZD), in acetonitrile (ACN)-aqueous solution and in mouse plasma. A Nova-Pak C18 reversed phase column (3.9mmx150mm, 4mum, 60A) was utilized in the separation using an isocratic mobile phase of 0.1% v/v triethylamine in phosphate buffer (pH=7.4): acetonitrile (ACN) (60:40, v/v), at a flow rate of 0.8mL/min. Detection wavelength was set at 310nm for both MK and AZD, and 431nm for the internal standard sunitinib (SUN). The developed method was validated following the ICH guidelines and it was shown to be accurate, precise and linear in the range of 41ng/mL to 8333ng/mL for both drugs in the ACN-aqueous solution and from 83ng/mL to 8333ng/mL for both drugs in mouse plasma samples. For the first time, the presented data suggest the suitability of this method for the simultaneous separation and quantification of MK and AZD in both ACN aqueous solution as well as in mouse plasma samples.
