| 名稱 | RO4987655 |
| 描述 | RO4987655 (RG7167) is an orally active and highly selective MEK inhibitor (IC50: 5.2 nM for MEK1/MEK2). |
| 細胞實驗 | Cells were treated with various concentrations of RO4987655 for 72 h in 96-well plates and viable cells were quantified with Cell Counting Kit-8. For Western blotting, cells were treated with RO4987655 for indicated periods and lysed with cell lysis buffer containing a protease inhibitor cocktail, phosphatase inhibitor cocktails 2 and 3, and 1 mM PMSF. For detection of protein bands, the following were used as primary antibodies: pEGFR, EGFR, pMKK4, MKK4, pAKT, AKT, pERK, ERK, pMEK1/2, MEK, Cyclin D1, and actin. All protein bands were visualized with secondary antibodies labeled with HRP and ECL system by using ImageQuant LAS 4000 [2]. |
| 動物實驗 | A time interval of 20 to 24 h was used between daily RO4987655 administration and completion of PET imaging for each tumor-bearing mouse and for each PET imaging time point (day 0, 1, 3 and 9). Mice were fasted for 6 to 8 h prior to start of the imaging session. [18F] FDG (7 to 8 MBq per mouse, maximum volume of 200 μL) was administered to awake, warmed (37°C) mice by a bolus injection via the tail vein. Forty to sixty minutes after the tracer injection, the mice were administered with isoflurane, controlled by an E-Z anesthesia vaporizer. The mice were placed on a heated pad (37°C) on the camera bed, with most of the body volume in the field of view (7.68 cm). Emission data were collected for 20 min in list mode with a microPET Focus 120 scanner. Maximum standardized uptake values (SUVmax) of [18F] FDG uptake in the tumor were calculated and normalized to the administered activity (MBq/body weight, g). The drug effect on tumor metabolism was estimated as%SUVmax change to day 0 (baseline) [2]. |
| 體外活性 | CH4987655 (RO4987655) 強效抑制有絲分裂原激活蛋白激酶信號通路的激活及腫瘤細胞生長，在體外對MEK1/2的抑制IC50為5.2 nmol/L [1]。在NCI-H2122細胞中，RO4987655在從0.1到1.0 μM的劑量范圍內(nèi)，治療開始后2小時就已顯著抑制pERK1/2。RO4987655以劑量依賴性方式抑制NCI-H2122細胞的增殖，IC50值為0.0065 μM [2]。 |
| 體內(nèi)活性 | 在劑量范圍研究中，以RO4987655 5.0 mg/kg治療，導(dǎo)致第1天FDG攝取顯著減少。隨后每天給予RO4987655，2.5 mg/kg治療，并在藥物給予的第1、3和9天進行PET檢查。最大降幅觀察于第1天，隨后第3天略有反彈。之后效果至第9天治療保持平穩(wěn)[2]。0.5、1、2、3和4 mg的劑量安全且耐受性良好。共報告26例不良事件（n=15），其中21例輕微，5例中度，無嚴(yán)重不良事件。1 mg劑量下一名受試者出現(xiàn)中度不良事件（自主神經(jīng)系統(tǒng)失衡），而在4 mg劑量下，三名受試者經(jīng)歷了中度不良事件（腹瀉、腹痛、自主神經(jīng)系統(tǒng)和痤瘡）[3]。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | DMSO : 35 mg/mL (61.92 mM), Sonication is recommended.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 2 mg/mL (3.54 mM), Sonication is recommended.
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| 關(guān)鍵字 | RO-4987655 | RO4987655 | RO 4987655 | RG-7167 | RG 7167 | Mitogen-activated protein kinase kinase | MEK2 | MEK1 | MEK | MAPKK | MAP2K | Inhibitor | inhibit | CH-4987655 | CH 4987655 |
| 相關(guān)產(chǎn)品 | Lidocaine hydrochloride | PD 198306 | Pelitinib | Lidocaine | Mirdametinib | Honokiol | Trilinolein | Lidocaine Hydrochloride hydrate | SCH772984 | AZD8330 | Selumetinib | trans-Zeatin |
| 相關(guān)庫 | 抑制劑庫 | 經(jīng)典已知活性庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 高選擇性抑制劑庫 | 抗卵巢癌化合物庫 | 免疫/炎癥分子化合物庫 | 疼痛相關(guān)化合物庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |