Background
RO4987655 is a highly selective and small molecule inhibitor of MEK with IC50 value of 5nM [1].
RO4987655 is developed with a unique 3-oxo-[1,2]oxazinan-2-ylmethyl group at the 5-position.It is highly selective against MEK over other 400 kinases. Meanwhile, RO4987655 is a non- competitive inhibitor of MEK. It shows higher affinity for MEK both in the absence and the presence of ATP. RO4987655 has a strong anti-proliferation efficacy in various tumor cells including COLO205, HT29, QG56, MIA and C32 with IC50 values of 0.86nM, 1.7nM, 9.5nM, 3.3nM and 8.4nM, respectively. In addition, RO4987655 is found to have antitumor activity in a wide range of human cancer xenograft models. In the HT-29 human colon cancer xenograft, RO4987655 shows a strong inhibition of pERK formation as well as tumor regression [1, 2].
RO4987655 is now in phase I trials. It shows clinical activity in both patients with BRAF wild-type melanoma and BRAF V600-mutated melanoma. It is also efficacious in patients with KRAS-mutated non-small cell lung cancer but not KRAS-mutated colorectal cancer [2].
参考文献:
[1] Isshiki Y, Kohchi Y, Iikura H, Matsubara Y, Asoh K, Murata T, Kohchi M, Mizuguchi E, Tsujii S, Hattori K, Miura T, Yoshimura Y, Aida S, Miwa M, Saitoh R, Murao N, Okabe H, Belunis C, Janson C, Lukacs C, Schück V, Shimma N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1795-801.
[2] Zimmer L, Barlesi F, Martinez-Garcia M, Dieras V, Schellens JH, Spano JP, Middleton MR, Calvo E, Paz-Ares L, Larkin J, Pacey S, Venturi M, Kraeber-Bodere F, Tessier JJ, Eberhardt WE, Paques M, Guarin E, Meresse Naegelen V, Soria JC. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected advanced cancer patients with RAS-RAF mutations. Clin Cancer Res. 2014 Jun 19. pii: clincanres.0341.2014.
Protocol
Cell experiment: | The human lung adenocarcinoma cell line NCI-H2122 are maintained in the designated media and indicated concentrations of heat-inactivated fetal bovine serum and L-glutamine. Cells are grown at 37°C in an atmosphere of 5%CO2. Cells are treated with various concentrations of RO4987655 (0.00001, 0.001, 0.1, and 10 μM) for 72 h in 96-well plates and viable cells were quantified with Cell Counting Kit-8[2]. |
Animal experiment: | Mice[2]Female athymic nude mice Balb nu/nu, age 5 to 6 weeks (18 to 22 g) are used. NCI-H2122 cells (4×106/mouse) are inoculated subcutaneously in the right flank of Balb-nu/nu mice. Once tumors are established (100 to 200 mm3), mice are randomized into groups with similar mean tumor volumes at the start of the study. The tumors size is estimated with digital caliper and PET scans performed on days 0, 1, and 3 with 1.0, 2.5, and 5.0 mg/kg RO4987655. Tumor volume and body weight are measured on days 0 (baseline), 1, 2, 3, and 9 of [18F] FDG-PET imaging. Tumor growth inhibition is calculated[2]. |
参考文献: [1]. Lee L, et al. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker. Clin Cancer Res. 2009 Dec 1;15(23):7368-74.
[2]. Tegnebratt T, et al. Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches. EJNMMI Res. 2014 Dec;4(1):34. |
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