Ilorasertib-ABT-348-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEIlorasertibCat. No.: HY-16018CAS No.: 1227939-82-3Synonyms: ABT-348分式: CHFNOS分量: 488.54作靶点: Aurora Kinase; VEGFR; PDGFR; RET作通路: Cell Cycle/DNA Damage; Epigenetics; Protein TyrosineKinase/RTK储存式: Please store the product under t

2、he recommended conditions inthe COA.溶解性数据体外实验 DMSO : 41.67 mg/mL (85.29 mM; Need ultrasonic)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (4.26 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (4.26 mM); Suspended solution; Need ultrasonic1/3

3、 Master of Small Molecules 您边的抑制剂师www.MedChemEBIOLOGICAL ACTIVITY物活性 Ilorasertib (ABT-348)种 ATP 竞争性的多靶点抑制剂，能够抑制 Aurora B/C/A，RET 酪氨酸激酶， PDGFR 和 Flt1 的活性，IC50 值分别为 7 nM，1 nM，120 nM，7 nM，3 nM 和 32 nM。IC50 & Target Aurora A Aurora B Aurora C Aurora B (Y156H)120 nM (IC50) 7 nM (IC50) 1 nM (IC50) 12 nM (

4、IC50)PDGFR PDGFR VEGFR1 VEGFR211 nM (IC50) 13 nM (IC50) 1 nM (IC50) 2 nM (IC50)VEGFR3 FLT3 CSF-1R c-KIT43 nM (IC50) 1 nM (IC50) 3 nM (IC50) 20 nM (IC50)体外研究 Ilorasertib is an ATP-competitive multitargeted kinase inhibitor with IC50 for inhibiting cellularautophosphorylation of Aurora B (13 nM), C (1

5、3 nM), and A (189 nM). In addition to targeting Aurora kinases,Ilorasertib is a potent inhibitor of the VEGFR and PDGFR kinase families and, to a lesser extent, the Srcfamily of cytoplasmic tyrosine kinases. Ilorasertib induces a concentration-dependent increase in the extentand number of two NSCLC

6、cell lines exhibiting polyploidy. The potency for inducing this response (EC50 = 5and 10 nM). Ilorasertib shows antiproliferative activity against BCR-ABL expressing CML cells and cellsexpressing the gleevec-resistant BCR-ABL T315I mutation (IC50 = 47 and 260 nM) 2.体内研究 Ilorasertib (25 mg/kg, s.c.)

7、leads to an inhibition of histone H3 phosphorylation in circulating tumor cellsobtained from an engrafted leukemia model. Ilorasertib inhibits the VEGF response with a potency (ED50 =0.2 mg/kg i.v.) in a uterine edema model. Ilorasertib (20 mg/kg, p.o.) inhibits the growth of established tumorsand c

8、auses regression of advanced tumors in human xenograft models 2. Ilorasertib demonstratessignificant antitumor efficacy in both solid and hematological xenograft models after intravenous, mini-pumpor parenteral once-weekly dosing 3.PROTOCOLCell Assay 2 Carcinoma cells (2500 cells/well) are plated ov

9、ernight in full-growth medium (containing 10% FBS).Compound is added to the cells in full-growth medium and incubated for 72 h at 37C in a CO2 incubator. Forleukemia cells, generally 50,000 cells/well are plated in full-growth medium, drug is added, and they areincubated for 72 h. The effects on pro

10、liferation are determined by the addition of alamarBlue (final solution10%), incubation for 4 h, and analysis in a fluorescence plate reader (excitation 544; emission 590), oralternatively, medium is removed and replaced with 200 L of Cell TiterGlo reagent and analyzed forluminescence. Noncycling pr

11、imary HUVEC are used to assess the effect of Ilorasertib on nonproliferatingcells. Cells (35,000/well) are seeded in growth medium in a 96-well tissue culture plate, and after 2 days, themedium is changed and the cells are treated with Ilorasertib. After an additional 3 days, cell viability ismeasur

12、ed with Cell TiterGlo reagent.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal sup2For flank xenograft models, cells are suspended in PBS, mixed with Matrigel (phenol red free) in a2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEAdministration ra

13、tio of 1:4 (v/v), and inoculated into the flank of female SCID/beige mice (5 million cells per site). Inoculatedmice are randomized into groups of 10, and treatment is initiated when mean tumor volume is approximately0.4 cm3 or 0.5 cm3. Tumor growth in the flank is assessed by measuring tumor size w

14、ith calipers andcalculating volume using the formula (L W2/2). Study groups are terminated before tumor volume reaches3 cm3. Inhibition of tumor growth is assessed at the time the vehicle-treated group is terminated bycalculating the ratio of the mean volume of the test drug group to the mean volume

15、 of the untreated (control)group (T/C) and calculating the percentage of inhibition of control (1 T/C) 100. The dosing formulation oftest agents is prepared by stepwise addition, with mixing, of the following reagents: EtOH, Tween 80,polyethylene glycol 400, and 2% hydroxypropyl methylcellulose (2:5

16、:20:73, v/v). Dosing volume is 10 mL/kg.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Gao C, et al. Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase. J MolModel. 2015 Jul;21(7):1

17、67.2. Glaser KB, et al. Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factorreceptor/platelet-derived growth factor receptor, and Src kinase families. J Pharmacol Exp Ther. 2012 Dec;343(3):617-27.3. Curtin ML, et al. Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinas