RO4987655 (RG7167) is an orally active and highly selective MEK inhibitor (IC50: 5.2 nM for MEK1/MEK2).

MEK1:5.2 nM (cell free), MEK2:5.2 nM (cell free)

CH4987655 (RO4987655) 强效抑制有丝分裂原激活蛋白激酶信号通路的激活及肿瘤细胞生长，在体外对MEK1/2的抑制IC50为5.2 nmol/L [1]。在NCI-H2122细胞中，RO4987655在从0.1到1.0 μM的剂量范围内，治疗开始后2小时就已显著抑制pERK1/2。RO4987655以剂量依赖性方式抑制NCI-H2122细胞的增殖，IC50值为0.0065 μM [2]。

在剂量范围研究中，以RO4987655 5.0 mg/kg治疗，导致第1天FDG摄取显著减少。随后每天给予RO4987655，2.5 mg/kg治疗，并在药物给予的第1、3和9天进行PET检查。最大降幅观察于第1天，随后第3天略有反弹。之后效果至第9天治疗保持平稳[2]。0.5、1、2、3和4 mg的剂量安全且耐受性良好。共报告26例不良事件（n=15），其中21例轻微，5例中度，无严重不良事件。1 mg剂量下一名受试者出现中度不良事件（自主神经系统失衡），而在4 mg剂量下，三名受试者经历了中度不良事件（腹泻、腹痛、自主神经系统和痤疮）[3]。

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].

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].