1、Product Data SheetCobimetinibCat. No.: HY-13064CAS No.: 934660-93-2分式: CHFINO分量: 531.31作靶點: MEK; Apoptosis作通路: MAPK/ERK Pathway; Apoptosis儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數據體外實驗 DMSO : 100 mg/mL (188.21 mM)* means soluble, but saturation unknown.SolventMass1 m

2、g 5 mg 10 mgConcentration制備儲備液1 mM 1.8821 mL 9.4107 mL 18.8214 mL5 mM 0.3764 mL 1.8821 mL 3.7643 mL10 mM 0.1882 mL 0.9411 mL 1.8821 mL請根據產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，避免反復凍融造成的產品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內使，-20C 儲存時，請在 1 個內使。體內實驗請根據您的實驗動物和給藥式選擇適當的溶解案。以下溶解案都請先按

3、照 In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實驗結果的可靠性，澄 的儲備液可以根據儲存條件，適當保存；體內實驗的作液，建議您現現配，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沉淀、析出現象，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 (4.71 mM); Clear solution此案可獲得 2.5 mg/mL (4.71 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100

4、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 (4.71 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (4.71 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 90

5、0 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 (4.71 mM); Clear solution此案可獲得 2.5 mg/mL (4.71 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 ACTIVITY物活性 Cobimetinib (GDC-0973, RG7420)有效，選擇性，可服的 MEK1 抑制劑，抑

6、制MEK1 的 IC50 為4.2 nM。IC & Target MEK14.2 nM (IC50)體外研究 The EC50 values of Cobimetinib (GDC-0973) for 888MEL and A2058 cells are 0.2 M, 10 M, respectivelly. Melanomacells are treated with EC50 concentration of MEK and PI3K inhibitors for 24 hours (888MEL: 0.05 M GDC-0973, 2.5 M GDC-0941; A2058: 2.5 M

7、 GDC-0973, 2.5 M GDC-0941)1. Mitochondrial OXPHOS limits cell death induced bycobimetinib (100 nM) in melanoma with constitutive MAPK activation in A375 cells4.體內研究 In the NCI-H2122 KRASG12C mutant non-small cell lung carcinoma (NSCLC) xenograft model, treatment with up to 5 mg/kg Cobimetinib (GDC-0

8、973) lead to moderate TGI and at 10 mg/kg approaches tumor stasis1. GDC-0973 and GDC-0941 are administered to A2058 tumor-bearing mice daily (QD) or every third day (Q3D) either as single agentsor in combination. The population rate constants associated with tumor growth inhibition for GDC-0973 and

9、GDC-0941 are 0.00102 and 0000651 M-1 h-1, respectively2. Following single doses of GDC-0973 (1, 3, or 10 mg/kg, p.o.)estimated in vivo IC50 values of %pERK decrease based on tumor concentrations in xenograft mice are 0.78 (WM-266-4) and 0.52 M (A375)3.PROTOCOLAnimal 5 million WM-266-4 melanoma cells

10、 are resuspended in Hank balanced salt solution and implanted intradermallyAdministration 3 into the hind flank of female NCR nude mice. On days 11 or 13 after the implantation, xenograft mice with tumorvolumes of approximately 100 to 120 mm3 are randomLy assigned to 8 groups (n=27 per group), 4 sin

11、gle dosegroups and 4 multiple dose groups. One day after randomization and group assignment, mice in the single dosegroups are given a single oral dose of vehicle (water for injection USP), 1, 3, or 10 mg/kg of Cobimetinib (GDC-0973,expressed as free base equivalents). Mice in the multiple dose grou

12、ps are given daily oral doses of vehicle (water forinjection USP), 1, 3, or 10 mg/kg of GDC-0973 for 14 days. Plasma and tumor samples (n=3 per time point) arecollected from euthanized mice predose and at 2, 4, 8, 16, 24, 72, 120, and 168 hours postdose on day 1 (single dosegroups) or day 14 (multip

13、le dose groups). Samples are stored at 80C until analysis. GDC-0973 concentrations inplasma and tumor lysates are determined using liquid chromatography/tandem mass spectrometry (LC/MS-MS). Thedynamic range of the assay is 0.004 to 35 M.MCE has not independently confirmed the accuracy of these metho

14、ds. They are for reference only.戶使本產品發表的科研獻Page 2 of 3 www.MedChemE Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Neuro Oncol. 2019 Mar 18;21(4):486-497. J Control Release. 2015 Oct 21;220(Pt A):160-168. Sci Signal. 2018 Oct 30;11(554). pii: eaar6795. Cancers (Basel). 2019 Feb 1;11(2). pii: E1

15、64.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Hoeflich KP, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growthinhibition. Cancer Res. 2012 Jan 1;72(1):210-9.2. Choo EF, et al. PK-PD

16、 modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 inA2058 xenografts. Cancer Chemother Pharmacol. 2013 Jan;71(1):133-43.3. Wong H, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, aMEK inhibitor. Clin Cancer Res. 2012 Jun 1;18(11):3090-9.4. Corazao-Rozas P, et al. Mitochondrial oxidative phosphorylation controls cancer cells life and death decisions upon exposure to MAPK inhibitors.Oncotarget. 2016 Feb 2