利尼伐尼作用机制 - Medchemexpress - MCE中国

1、Product Data SheetLinifanibCat. No.: HY-50751CAS No.: 796967-16-3分式: CHFNO分量: 375.4作靶点: PDGFR; VEGFR; FLT3; c-Fms; c-Kit; Autophagy; Apoptosis作通路: Protein Tyrosine Kinase/RTK; Autophagy; Apoptosis储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 72 mg/mL (191.80

2、mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg 10 mgConcentration制备储备液1 mM 2.6638 mL 13.3191 mL 26.6383 mL5 mM 0.5328 mL 2.6638 mL 5.3277 mL10 mM 0.2664 mL 1.3319 mL 2.6638 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 储存时，请在 6

3、 个内使，-20C 储存时，请在 1 个内使。体内实验请根据您的实验动物和给药式选择适当的溶解案。以下溶解案都请先按照 In Vitro 式配制澄清的储备液，再依次添加助溶剂：为保证实验结果的可靠性，澄 的储备液可以根据储存条件，适当保存；体内实验的作液，建议您现现配，当天使； 以下溶剂前显的百分 指该溶剂在您配制终溶液中的体积占；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的式助溶1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.66 mM); Clear soluti

4、on此案可获得 2.5 mg/mL (6.66 mM，饱和度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 400 L PEG300 中，混合均匀；向上述体系中加50 L Tween-80，混合均匀；然后继续加 450 L 理盐定容 1 mL。2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.66 mM); Clear solutionPage 1 of 2 www.MedChemE此案可获得 2.5 mg/mL (6.66 mM，饱和

5、度未知) 的澄清溶液。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L 20% 的 SBE-CD 理盐溶液中，混合均匀。3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.66 mM); Clear solution此案可获得 2.5 mg/mL (6.66 mM，饱和度未知) 的澄 溶液，此案不适于实验周 期在半个以上的实验。以 1 mL 作液为例，取 100 L 25.0 mg/mL 的澄 DMSO 储备液加到 900 L 油中，混合均匀。BIOLOGICAL ACTIV

6、ITY物活性 Linifanib (ABT-869)种效、服的 VEGFR 和 PDGFR 家族多靶点抑制剂，对 KDR、FLT1、PDGFR、FLT3 的 IC50s 分别为 4、3、66、4 nM。Linifanib (ABT-869) 具有显著的抗肿瘤活性。Linifanib (ABT-869) 对关 RTKs、可溶性酪氨酸激酶或丝氨酸/苏氨酸激酶的活性要低得多。IC & Target KDR PDGFR Flt-1 FLT34 nM (IC50) 66 nM (IC50) 3 nM (IC50) 4 nM (IC50)CSF-1R Kit3 nM (IC50) 14 nM (IC50)

7、体外研究 Linifanib exhibits IC50 values that range from 4 nM (KDR) to 190 nM (FLT4) for members of the VEGF and PDGFreceptor families. Linifanib is also active against TIE2 and, to a lesser extent, RET, but is much less active (IC5010 M)against other nonrelated tyrosine kinases, such as steroid receptor

8、 coactivator and epidermal growth factor receptor.Phosphorylation of KDR induced by VEGF is inhibited by Linifanib with an IC50 of 4 nM in 3T3 murine fibroblastsengineered to express human KDR. A similar potency for inhibition of receptor autophosphorylation is seen withLinifanib when HUAECs are use

9、d as the target cell. Linifanib inhibits VEGF-stimulated phosphorylation of KDRcompletely at 10 nM and by 70% at 3 nM (IC50=2 nM)1.体内研究 Linifanib is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50=0.5 mg/kg)and corneal angiogenesis (50% inhibition, 15 mg/kg)

10、. ABT-869 exhibits efficacy in human fibrosarcoma and breast,colon, and small cell lung carcinoma xenograft models (ED50=1.5-5 mg/kg, twice daily) and is also effective (50%inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression is observed inepidermoid carci

11、noma and leukemia xenograft models, respectively1.PROTOCOLKinase Assay 1 For tyrosine kinase assays, a biotinylated peptide substrate containing a single tyrosine is used with 1 mM ATP, anEu-cryptate-labeled anti-phosphotyrosine antibody (PT66), and Strepavidin-APC in a homogeneous timeresolvedfluor

12、escence assay. Serine/threonine kinases are assayed using 5 M ATP, 33PATP, and a biotinylated peptidesubstrate with peptide capture and incorporation of 33P determined using a SA-Flashplate. Linifanib is assayed atmultiple concentrations prepared by serial dilution of a DMSO stock solution of the co

13、mpound. The concentrationresulting in 50% inhibition of activity is calculated using nonlinear regression analysis of the concentration responsedata1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 HUAEC are plated into 96-well plates at 2,

14、500 per well and incubated with serum-free medium for 24 hours. Linifaniband VEGF(final, 10 ng/mL) are added and incubated for 72 hours in serum-free medium. For carcinoma cell lines,Page 2 of 3 www.MedChemE2,500 per well are plated overnight in full growth medium. Linifanib is added to the cells in

15、 full growth medium andincubated for 72 hours. For leukemia cells, generally 50,000 per well are plated in full growth medium, drug added,and incubated for 72 hours. The effects on proliferation are determined by addition of Alamar Blue (final solution,10%), incubation for 4 hours at 37jC in a CO2 i

16、ncubator, and analysis in a fluorescence plate reader1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice: Tumor-bearing animals are divided into groups (n=10), and administration of vehicle (2% ethanol, 5% TweenAdministration 1 80, 20% PEG400,

17、 73% saline) or inhibitor (Linifanib) at the indicted dose is initiated. Tumor growth in the flank isassessed by measuring tumor size with calipers and calculating size. Tumor volume for the orthotopic glioma modelis determined using magnetic resonance imaging1.MCE has not independently confirmed th

18、e accuracy of these methods. They are for reference only.户使本产品发表的科研献 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Nat Biomed Eng. 2018;2:578-588. Int J Oncol. 2019 Oct;55(4):879-895. Harvard Medical School LINCS LIBRARYSee more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Albert DH, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine