洛那法尼作用機制 - Medchemexpress - MCE中國

1、Product Data SheetLonafarnibCat. No.: HY-15136CAS No.: 193275-84-2分式: CHBrClNO分量: 638.82作靶點: Farnesyl Transferase; Autophagy; Influenza Virus作通路: Metabolic Enzyme/Protease; Autophagy; Anti-infection儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 100 mg/mL (156.

2、54 mM)* means soluble, but saturation unknown.SolventMass1 mg 5 mg 10 mgConcentration制備儲備液1 mM 1.5654 mL 7.8269 mL 15.6539 mL5 mM 0.3131 mL 1.5654 mL 3.1308 mL10 mM 0.1565 mL 0.7827 mL 1.5654 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備液；旦配成溶液，請分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在

3、 6 個內(nèi)使，-20C 儲存時，請在 1 個內(nèi)使。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當?shù)娜芙獍?。以下溶解案都請先按?In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結(jié)果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當天使； 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；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (3.91 mM); Clear solu

4、tion此案可獲得 2.5 mg/mL (3.91 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. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (3.91 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (3.91 mM，

5、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 儲備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (3.91 mM); Clear solution此案可獲得 2.5 mg/mL (3.91 mM，飽和度未知) 的澄 溶液，此案不適于實驗周 期在半個以上的實驗。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACT

6、IVITY物活性 Lonafarnib種服有效的法尼 蛋轉(zhuǎn)移酶 (FPTase) 抑制劑，作于 H-ras，K-ras 和 N-ras，IC50 分別為 1.9 nM，5.2 nM 和 2.8 nM。Lonafarnib 具有抗肝炎三洲病毒 (HDV) 的活性。IC & Target IC50: 1.9 nM (H-ras), 5.2 nM (K-ras), 2.8 nM (N-ras)1體外研究 Lonafarnib (Sch66336) potently inhibits Ha-Ras processing in whole cells and blocks the trans forme

7、d growthproperties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins1. All treatment groupscontaining Lonafarnib (10 M) show a significantly higher level of unfarnesylated H-Ras (116-137%) compared tocontrol treatment2.體內(nèi)研究 In mouse, rat, and monkey systems, Lonafarnib (

8、Sch66336) has excellent oral bioavailability and pharmacokineticproperties. In the nude mouse, Lonafarnib demonstrates potent oral activity in a wide array of human tumorxenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin1. Lonafarnib alone(80 mg/kg by or

9、al gavage, once daily) has limited ability to inhibit orthotopic U87 tumors compared to vehicletreated control animals (T/C of 0.67). The combination of XRT/Tem (2.5Gy/day for 2 days; 5 mg/kg by oral gavage 90min prior to XRT) is designed to produce modest tumor growth inhibition in vivo(T/C of 0.42

10、). ConcurrentLonafarnib/XRT/Tem (Lonafarnib 80 mg/kg by oral gavage, once daily, XRT 2.5Gy/day for 2 days, and Tem 5 mg/kg byoral gavage 90 min prior to XRT) provides the strongest growth reduction (T/C of 0.02) and is significantly moreeffective than XRT/Tem (p0.04), with the majority of animals de

11、monstrating a decrease in tumor volume (p0.05)after two weeks and persisting after 4 weeks (p0.05)2.PROTOCOLKinase Assay 1 FPTactivity is determined by measuring the transfer of 3Hfarnesyl from 3Hfarnesyl PPi to trichloroacetic acid-precipitable Ha-Ras-CVLS. GGPT-1 activity is similarly determined u

12、sing 3Hgeranylgeranyl diphosphate and Ha-Ras-CVLL as substrates1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 2 CellTiter96 Aqueous Assay kit is used. Assays are performed with 5000 cells/well in a 96-well tissue culture plate.Plates are i

13、rradiated 24 h after drug exposure and assayed 96 h after XRT, with fresh drug treatments applied eachday. For quantification, dye is added directly to each well, plates are washed as per the manufacturesrecommendation and cell viability determined by optical density. Significance is analyzed using

14、the Students T-test.12-well plates are seeded with 100,000 cells/well. Drug treatments are initiated 24 h after plating, and media isreplaced every 24 h for a total of 96 h of drug exposure. Plates are irradiated after 24 h of drug exposure. Cells fromtriplicate sets of treatments are trypsonized an

15、d counted 48 h after irradation using a Z1 series coulter counter, andcompared to cell numbers from wells counted on Day 1 (the day drug treatment is initiated). Proliferation after drugtreatments are normalized to the control wells and expressed as % of the control treatment. Significance is analyz

16、edPage 2 of 3 www.MedChemEusing the Students T-test2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice2Administration 2 Lonafarnib is given once daily at 80mg/kg with twice weekly weightings to ensure accurate dosing. Temozolomide(Tem) is give

17、n by gavage at 5 mg/kg 90 min prior to XRT. For irradiation, anesthetized mice are placed in a leadshielding apparatus which limited radiation exposure to the head only. Treatment (2.5Gy/day for two days) isdelivered using a Gammacell 40 irradiator delivering 100 rads/min. For in vivo combination ex

18、periments, suboptimaldoses of XRT/Tem are selected to permit identification of synergistic effects of Lonafarnib.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 Nat Commun. 2019 May 22;10(1):2265. Aging Cell. 2019 Aug;18(4):e12979. Sci Rep.

19、2019 Jul 10;9(1):10021. Med Mycol. 2018 Jun 1;56(4):452-457.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Liu M, et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft modelsand wap-ras transgenic mice. Cancer Res. 1998 N