AZD-7762 _Chk 抑制劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAZD-7762Cat. No.: HY-10992CAS No.: 860352-01-8分式: CHFNOS分量: 362.42作靶點(diǎn): Checkpoint Kinase (Chk)作通路: Cell Cycle/DNA Damage儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 100 mg/mL (275.92 mM;

2、 Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.7592 mL 13.7961 mL 27.5923 mL5 mM 0.5518 mL 2.7592 mL 5.5185 mL10 mM 0.2759 mL 1.3796 mL 2.7592 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和期限。體內(nèi)實(shí)驗(yàn) 請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前?qǐng)先配制澄清的儲(chǔ)備液，再依次添加助溶劑(為保證實(shí)驗(yàn)結(jié)果的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲(chǔ)備液可

3、以根據(jù)儲(chǔ)存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.90 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.90 mM); Clear solution3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.9

4、0 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEBIOLOGICAL ACTIVITY物活性 AZD-7762種有效的ATP競(jìng)爭(zhēng)性的細(xì)胞周 期檢測(cè)點(diǎn)激酶 (checkpoint kinase，Chk) 抑制劑，抑制Chk1的IC50 為 5 nM。IC50 & Target Chk1 Chk25 nM (IC50) 5 nM (IC50)體外研究 AZD-7762 (AZD7762) is an equally potent inhibitor of Chk1 and Chk2 in vitro. AZ

5、D-7762 potently inhibitsChk1 and Chk2, abrogates DNA damage-induced S and G2 checkpoints, enhances the efficacy ofgemcitabine and topotecan, and modulates downstream checkpoint pathway proteins. AZD-7762 potentlyinhibits Chk1 phosphorylation of a cdc25C peptide with an IC50 of 5 nM as measured by a

6、scintillationproximity assay. The Ki for AZD-7762 is determined to be 3.6 nM. Kinetic characterization suggests thatAZD-7762 binds in the ATP-binding site of Chk1 and is thought to compete directly for ATP binding in areversible manner. AZD-7762 is shown to abrogate the G2 arrest induced by Camptoth

7、ecin with an averageEC50 of 10 nM (n=12) and maximal abrogation in the range of 100 nM 1.體內(nèi)研究 In the rat H460-DNp53 xenograft study, AZD-7762 (AZD7762) potentiates the antitumor activity ofGemcitabine in a dose-dependent manner by a decrease in %T/C with increasing dose (48% and 32%, 10and 20 mg/kg

8、AZD-7762, respectively). In the mouse xenograft study in combination with Irinotecan, SW620established tumors are treated with vehicle, Irinotecan alone, AZD-7762 alone, or AZD-7762 in combinationwith Irinotecan. AZD-7762 dosed alone shows insignificant antitumor activity, whereas Irinotecan alonedi

9、splays striking and significant activity (%T/C with increasing dose is 9 and 1, respectively ). In combinationwith AZD-7762, %T/C increases significantly to -66% and -67%, respectively 1. AZD7762 combination withCX-5461 induces cancer cell death of Tp53-null (Tp53-/-) E-Myc lymphoma cells in vitro a

10、nd in vivo 2.PROTOCOLKinase Assay 1 For kinetic analysis, a filter binding assay is used. The assay reaction contains with the followingconcentrations of ATP 0-600 M (cold+Ci 33PATP), determined Km, Chk1 (0.5 nM), and AZD-7762 (0,1.5, 5, 10 nM). The reaction is incubated at room temperature for 20 m

11、in, stopped by the addition of EDTA,transferred to Streptavidin Flashplate, incubated at room temperature for 1 h, aspirated out, and wellswashed with PBS. Plates are counted using a TopCount reader and data are analyzed using proprietarysoftware 1.MCE has not independently confirmed the accuracy of

12、 these methods. They are for reference only.Cell Assay 1 SW620 (5.5103 per well) or MDA-MB-231 (5103 per well) cells are seeded in 96-well plates and incubatedovernight. Cells are dosed for 24 h with a 9-point titration of Gemcitabine ranging from 0.01 to 100 nM with orwithout a constant dose of AZD

13、-7762 (300 nM). Control wells are dosed with vehicle alone (0.1% DMSO) or300 nM AZD-7762. After 24 h, medium is removed and AZD-7762 alone is added back to the wells treatedpreviously with AZD-7762 for an additional 24 h. Cells are then incubated in drug-free medium for anadditional 72 h. The effect

14、 on cell proliferation is determined by MTS assay 1.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEMCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice and Rats 1Administration 12 Male NCr mice and male rnu rats are used. For xenograft models i

15、n mice, tumor cells are harvested, pelletedby centrifugation for 5 min, and resuspended in sterile PBS. Cells (3103-6106) are implanted s.c. into theright flank of the mice in a volume of 0.1 to 0.2 mL using a 25-gauge needle. Tumors are allowed to grow tothe designated size of 100 to 200 mm3 before

16、 the administration of compound. For xenograft models in rats,Cells are harvested, pelleted by centrifugation for 5 min, and resuspended in 50% sterile PBS and 50%Matrigel. Rats receive a 5 Gy whole-body radiation dose 5 days before cell implantation to improve tumorgrowth. H460-DNp53 cells (1107) a

17、re implanted s.c., under anesthesia with isoflurane, into the right flank ofthe rats in a volume of 0.2 mL using a 25-gauge needle. Tumors are allowed to grow to the designated sizeof 100 to 200 mm3 before the administration of AZD-7762. AZD-7762 (10 and 20 mg/kg) is administered byi.v. injection vi

18、a the tail vein. Cyclic schedules are used and treatment ranged from three to five cycles. Eachcycle includes administration of a standard agent (Gemcitabine or Irinotecan) every 3 days follow by deliveryof AZD-7762. Tumor volumes are measured with electronic calipers and calculated.Mice 2C57Bl/6 mi

19、ce are intravenously injected with 2105 E-Myc B-lymphoma cells in PBS and treated withpharmacological inhibitors from 8 days post-injection. Treatment of mice is continued until an ethical end-point is reached; hunched posture, ruffled fur, enlarged lymph nodes, laboured breathing, weight loss great

20、erthan 20% of start body weight and limited mobility or paralysis. AZD7762 is delivered intraperitoneally in10.3% -hydroxypropyl-cyclodextrin in 0.9% saline at 20 mg/kg daily on weekdays.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. PLoS One. 2019 Jan 10;14(1):e0209224. PLoS One. 2017 Jan 18;12(1):e0170308. FEBS Let