德立替尼作用機(jī)制 - Medchemexpress - MCE中國(guó)

1、Product Data SheetLucitanibCat. No.: HY-15391CAS No.: 1058137-23-7分式: CHNO分量: 443.49作靶點(diǎn): VEGFR; FGFR作通路: Protein Tyrosine Kinase/RTK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 : 25 mg/mL (56.37 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg 1

2、0 mgConcentration制備儲(chǔ)備液1 mM 2.2548 mL 11.2742 mL 22.5484 mL5 mM 0.4510 mL 2.2548 mL 4.5097 mL10 mM 0.2255 mL 1.1274 mL 2.2548 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；旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?6 個(gè)內(nèi)使，-20C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?1 個(gè)內(nèi)使。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)娜芙獍浮Ｒ韵氯芙獍付颊?qǐng)先按照 In Vi

3、tro 式配制澄清的儲(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，澄 的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的式助溶1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.64 mM); Clear solution此案可獲得 2.5 mg/mL (5.64 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0

4、mg/mL 的澄 DMSO 儲(chǔ)備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.64 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (5.64 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 20%

5、 的 SBE-CD 理鹽溶液中，混合均勻。3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.64 mM); Clear solution此案可獲得 2.5 mg/mL (5.64 mM，飽和度未知) 的澄 溶液，此案不適于實(shí)驗(yàn)周 期在半個(gè)以上的實(shí)驗(yàn)。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Lucitanib (E-3810)是VEGFR 和 FGFR 的雙重 抑制劑，有效和選擇性地抑制VEGFR1，VE

6、GFR2，VEGFR3，F(xiàn)GFR1，F(xiàn)GFR2，IC50分別為7 nM，25 nM，10 nM，17.5 nM，82.5 nM。IC & Target VEGFR1 VEGFR2 VEGFR3 FGFR17 nM (IC50) 25 nM (IC50) 10 nM (IC50) 17.5 nM (IC50)FGFR282.5 nM (IC50)體外研究 Consistent with the inhibitory activity of VEGFR and FGFR auto-phosphorylation, Lucitanib potently inhibits VEGF andbFGF-s

7、timulated HUVEC proliferation with IC50 of 40 and 50 nM, respectively. Besides, Lucitanib (E-3810) also inhibitsCSF-1R with IC50 of 5 nM1. Lucitanib potently inhibits FGFR2 activity (Ki0.05 M), follows by PDGFR activity (Ki=0.11 M). The Ki values obtained for DDR2, LYN, CARDIAK, CSBP (2), EPHA2, and

8、 YES range between 0.26 and 8 M2.體內(nèi)研究 Lucitanib (E-3810), at oral dosing of 20 mg/kg for 7 consecutive days, completely inhibits (P0.01) the bFGF inducedangiogenic response compare with the response in vehicle-treated mice. Lucitanib (E-3810) shows a broad spectrumof activity, being active in all th

9、e xenografts tested (HT29 colon carcinoma, A2780 ovarian carcinoma, A498, SN12K1,and RXF393 renal carcinomas) with dose-dependent inhibition of tumor growth. E-3810 significantly delays growthduring treatment, but tumors resume their growth when treatment is suspended; in a few cases, tumor regressi

10、on isobserved1. The activity of Lucitanib (E-3810) given at the doses of 15 mg/kg is tested on MDA-MB-231 breast cancertransplanted subcutaneously, at a late stage, when tumor masses reach 350 to 400 mg. This tumor xenograft is verysensitive to Lucitanib (E-3810), with complete tumor stabilization l

11、asting throughout the 30-day treatment. As in othertumor models, tumors re-grow after withdrawal of Lucitanib (E-3810) at a rate similar to control tumors3.PROTOCOLCell Assay 1 Exponentially growing HUVEC or NHI3T3 cells are seeded into 96-well plates at a density of 3 to 6103 cells/100 L/well in co

12、mplete medium. In the experiments without serum starvation, 24 hours after seeding, cells are exposed todifferent Lucitanib (E-3810) concentrations without or with VEGF165 (50 ng/mL) or bFGF (20 ng/mL) ligands and theantiproliferative effect of the drugs is evaluated after 72 hours by MTS Colorimetr

13、ic Assay. In the assays with serumstarvation conditions, 24 hours after seeding complete medium is removed and after 3 rounds of washing with PBS,cells are cultured in medium containing 1% BSA. After 18 to 24 hours, cells are processed. Exponentially growingA2780, A498, SN12KI, and HepG2 cells are s

14、eeded into 96-well plates at 3 to 5103 cells/100 L/well in completemedium. Twenty-four hours later cells are treated with different drug concentrations for 72 hours and theantiproliferative effect is evaluated by MTS1.MCE has not independently confirmed the accuracy of these methods. They are for re

15、ference only.Page 2 of 3 www.MedChemEAnimal Mice3Administration 2 MDA-MB-231 tumor-bearing mice are randomized when their tumor masses are about 350 to 400 mg to receiveLucitanib (E-3810) (15 mg/kg), Brivanib, and Sunitinib at the doses used for the antitumor activity trial, for 10 days.Four hours a

16、fter the antiangiogenic dose of day 7, Paclitaxel is injected intravenously at the dose of 20 mg/kg andtumor and plasma samples are collected after 1, 4, and 24 hours in all the groups (each group consisting of 3animals). At the indicated sampling time, mice are anesthetized, blood is collected from

17、 the retro-orbital plexus intoheparinized tubes, and the plasma fraction is separated. Mice are killed by cervical dislocation, and tumors excisedand snap-frozen. The samples are analyzed by high-performance liquid chromatography (HPLC) with UV detection at230 nm.MCE has not independently confirmed

18、the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Science. 2017 Dec 1;358(6367). pii: eaan4368. Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Bello E, et al. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb15;71(4):1