1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEQuizartinibCat. No.: HY-13001CAS No.: 950769-58-1Synonyms: AC220分式: CHNOS分量: 560.67作靶點(diǎn): FLT3; Autophagy作通路: Protein Tyrosine Kinase/RTK; Autophagy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) DM

2、SO : 33 mg/mL (58.86 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 1.7836 mL 8.9179 mL 17.8358 mL5 mM 0.3567 mL 1.7836 mL 3.5672 mL10 mM 0.1784 mL 0.8918 mL 1.7836 mL請根據(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，并請注意儲(chǔ)備液的保存式和期限。體內(nèi)實(shí)驗(yàn) Quizartinib (AC220) is prepared in ve

3、hicle (22% hydroxypropyl-cyclodextrin in sterile water)2.BIOLOGICAL ACTIVITY物活性 Quizartinib (AC220)種有效的 Flt3 酪氨酸激酶抑制劑，Kd值為1.60.7 nM。IC50 & Target Kd: 1.60.7 nM (Flt3) 11/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE體外研究 Quizartinib (AC220) is a novel compound expressly optimized as a FLT3 inhibito

4、r for the treatment of acutemyeloid leukemia (AML). Quizartinib inhibits FLT3-WT and FLT3-ITD autophosphorylation with IC50 of4.20.3 nM and 1.10.1 nM, respectively. Quizartinib inhibits MV4-11 and A375 cells with IC50 of 0.560.3nM and 10 000 nM, respectively. Quizartinib inhibits FLT3 with low nanom

5、olar potency in cellular assaysand is highly selective when screened against the majority of the human protein kinome 1.體內(nèi)研究 Quizartinib (AC220) inhibits FLT3 activity in vivo, significantly extends survival in a mouse model of FLT3-ITDAML at doses as low as 1 mg/kg when dosed orally once a day, era

6、dicates tumors in a FLT3-dependentmouse xenograft model at 10 mg/kg, and potently inhibits FLT3 activity in primary patient cells. The oralbioavailability of Quizartinib, determined in rats by comparing oral and intravenous pharmacokinetics at 3mg/kg, is approximately 40%. A single 10 mg/kg dose of

7、Quizartinib is administered by oral gavage, andmice are killed at 2 time points after dosing, using groups of 4 animals each. Quantitation of total FLT3 andphospho-FLT3 in tumor samples revealed time-dependent inhibition of FLT3 autophosphorylation. FLT3activity is inhibited by 90% at 2 hours, and 4

8、0% at 24 hours after administration. The extent of inhibitiontherefore correlated well with the expected free Quizartinib plasma levels, based on pharmacokineticexperiments 1.PROTOCOLKinase Assay 1 KinomeScan kinase binding assays are performed. For the FLT3 assay, a kinase construct that spanned th

9、ecatalytic domain only (amino acids 592 to 969) is used. This construct does not include the juxtamembranedomain and is designed to measure the intrinsic binding affinity of the open FLT3 active site for inhibitors 1.MCE has not independently confirmed the accuracy of these methods. They are for ref

10、erence only.Cell Assay 1 MV4-11 and RS4;11 cells are cultured in Iscove media with 10% fetal bovine serum (FBS) and RPMIcomplete with 10% FBS, respectively. For proliferation assays, cells are cultured overnight in low serummedia (0.5% FBS), then seeded in a 96-well plate at 40 000 cells per well. I

11、nhibitors (e.g., Quizartinib) areadded to the cells and incubated at 37C for 72 hours. Cell viability is measured using the Cell Titer-Blue CellViability Assay. To measure inhibition of FLT3 autophosphorylation, cells are cultured in low serum media(0.5% FBS) overnight and seeded at a density of 400

12、 000 cells per well in a 96-well plate the following day.The cells are incubated with inhibitors (e.g., Quizartinib) for 2 hours at 37C. To induce FLT3autophosphorylation in RS4;11 cells, 100 ng/mL FLT3 ligand is added for 15 minutes after the 2-hourcompound incubation. Cell lysates are prepared and

13、 incubated in 96-well plates precoated with a total FLT3capture antibody. The coated plates are incubated with either a biotinylated antibody against FLT3 to detecttotal FLT3 or an antibody against phosphotyrosines to detect FLT3 autophosphorylation. In both cases, aSULFO-tagged streptavidin seconda

14、ry antibody is used for electrochemiluminescence detection on the MesoScale Discovery platform 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 Female NU/NU or severe combined immunodeficient mice are used. Quizartinib (hy

15、drochloride salt) isformulated in 22% hydroxypropyl-cyclodextrin, CEP-701 is formulated in 20% gelucire 44/14 in water(vol/vol), MLN-518 and SU 11248 are formulated in 10 mM sodium citrate (pH 3.5), PKC-412 is formulated in2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE3:1 gelucire 44/14-propylene

16、 glycol (vol/vol), and Bay 43-9006 is formulated in 80% PEG-400. Compoundconcentrations are chosen to deliver the desired dose in a volume of 10 mL/kg. Compounds are administeredby oral gavage and plasma samples collected 0.25, 0.5, 1, 2, 4, 6, and 24 hours after dosing. To collectplasma samples, ey

17、e bleeds (150 L) are taken semilongitudinally using 3 groups of 3 animals each, taking 2to 3 time points per animal to obtain a total of 3 independent plasma concentration time courses. Plasmasamples and controls (25 L) are extracted with 4 volumes of acetonitrile containing an internal standard and

18、analyzed by liquid chromatography tandem mass spectrometry.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) Cancer Cell. 2018 Oct 8;34(4):674-689.e8. Cancer Cell. 2014 Feb 10;25(2):226-42. Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Nat Commun. 2018 Jan 24;9(1):358