ARS-1620 - Ras 抑制劑 - 生命科學試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEARS-1620Cat. No.: HY-U00418CAS No.: 1698055-85-4分式: CHClFNO分量: 430.84作靶點: Ras作通路: GPCR/G Protein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 : 53 mg/mL (123.02 mM)* means soluble, but satu

2、ration unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.3210 mL 11.6052 mL 23.2105 mL5 mM 0.4642 mL 2.3210 mL 4.6421 mL10 mM 0.2321 mL 1.1605 mL 2.3210 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，并請注意儲備液的保存式和期限。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?，配制前請先配制澄清的儲備液，再依次添加助溶?為保證實驗結(jié)果的可靠性，體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當天使；澄清的儲備液可以根據(jù)

3、儲存條件，適當保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (4.83 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (4.83 mM); Clear solution3. 請依序添加每種溶劑： 10% DMSO 90% corn oil1/3 Master of Small Molecul

4、es 您邊的抑制劑師www.MedChemESolubility: 2.08 mg/mL (4.83 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 ARS-1620種阻轉(zhuǎn)異構(gòu)且有選擇性的 KRASG12C 抑制劑，具有理想的藥代動學。IC50 & Target KRAS(G12C)體外研究 ARS-1620 is an atropisomeric selective KRASG12C inhibitor with desirable pharmacokinetics. ARS-1620exhibits complete growth suppression

5、 of p.G12C cell lines (IC50=150 nM) with relatively benign effects oncontrol cell lines. It is found that ARS-1620 significantly reduces expression of the gene set in p.G12C mutantcells in a time-dependent manner but not in the p.G12S mutant cells. Following a 5-day treatment period,only a minority

6、of G12C mutant cell lines are sensitive to ARS-1620 under monolayer culture conditions,whereas in 3D-spheroid conditions, ARS-1620 elicits a robust response (p=0.0140) 1.體內(nèi)研究 Following a single oral dose or 5 consecutive daily doses, ARS-1620 yields average peak tumorconcentrations of 1.5 M (50 mg/k

7、g) and 5.5 M (200 mg/kg), respectively, that enables significantKRASG12C target occupancy (=70% G12C-TE at 200 mg/kg) for 24 hr. In MIAPaCa2 xenografts(p.G12C), ARS-1620 significantly inhibits tumor growth (p0.001) in a dose-dependent manner with markedregression at a dose of 200 mg/kg, given once d

8、aily. Across all tumor models employed, ARS-1620 is welltolerated over the entire 3-week treatment period. Moreover, there are no observed clinical signs or toxicity ofARS-1620 in CD-1 mice even at oral doses up to 1,000 mg/kg administered daily over a 7-day period.PROTOCOLCell Assay 1 5104 cells ar

9、e seeded into 24 well ULA-plates and allowed to rest overnight. Cells are then treated withDMSO or ARS-1620. After 2 days of treatment, apoptosis and cell death is measured by staining withannexinV-APC and prodidium iodide or by 70% ethanol fixation followed by FxCycle Violet staining tomeasure DNA

10、content (cell cycle) and percentage of sub-diploid events by flow cytometry 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal For pharmacokinetic (PK) studies 6- to 8-week-old male BALB/c mice are used. To determine oralAdministration 1 bioavaila

11、bility, mice are treated with ARS-1620 by a single intravenous (IV) bolus or oral gavageadministration at the doses of 2 and 10 mg/kg, respectively. ARS-1620 concentration in plasma is quantifiedby LC-MS/MS-based methods. Pharmacokinetic parameters are estimated from mean plasma concentration-time p

12、rofiles. The area under the curve (AUC) is calculated from time versus concentration data using thelinear trapezoidal rule. The oral bioavailability is calculated as the ratio of AUC for ARS-1620 from oral and IVdosage. The calculation is normalized by relative doses 1.MCE has not independently conf

13、irmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE Nat Med. 2019 Apr;25(4):628-640. Biomedical Engineering. Virginia Commonwealth University. 2019 May.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Janes MR, et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell. 2018 Jan 25;172(3):578-589.e17.M