FR 180204 is a selective ERK inhibitor with IC50 values of 0.51μM and 0.33μM for ERK1 and ERK2, respectively [1]. FR 180204 can induce the activation of AP-1 by TGF-β (IC50=3.1µM), and inhibit the activity of ERK by binding to the Q105, D106, L156, and C166 sites of the active pocket [2]. FR 180204 has been widely used to inhibit endothelial cell migration and angiogenesis[3].
In vitro, FR 180204 treatment for 48 hours significantly inhibited the viability of DLD-1 cells and LoVo cells, with IC50 values of 150µM and 40µM, respectively[4]. Treatment with 50µM FR 180204 for 16 hours significantly inhibited the activity of heme oxygenase (HO) and lactate dehydrogenase in mouse glial cortical cells[5].
In vivo, FR 180204 treatment via intraperitoneal injections at a dose of 100mg/kg (twice a day) for 12 days ameliorated collagen-induced arthritis in mice and decreased weight loss[6]. Intravenous injection of FR 180204 at a dose of 50mg/kg at 1 hour before, 1 hour after, and 24 hours after dengue virus (DENV) infection significantly ameliorated DENV-induced liver injury and hematological parameters in Balb/c mice [7]. Continuous intraperitoneal injection of a 100mg/kg/day dose of FR 180204 for one week significantly alleviated myocardial hypertrophy induced by isoproterenol (ISO) in Pak-1 knockout mice[8].
References:
[1] Lee C J, Lee H S, Ryu H W, et al. Abstract A24: Targeting of ERKs with magnolin inhibits EGF-induced anchorage-independent cell transformation[J]. Cancer Prevention Research, 2013, 6(11_Supplement): A24-A24.
[2] Ohori M, Kinoshita T, Okubo M, et al. Identification of a selective ERK inhibitor and structural determination of the inhibitor–ERK2 complex[J]. Biochemical and biophysical research communications, 2005, 336(1): 357-363.
[3] Xue S, Tang H, Zhao G, et al. CC Motif Chemokine 8 promotes angiogenesis in vascular endothelial cells[J]. Vascular, 2021, 29(3): 429-441.
[4] Saglam A S Y, Alp E, Elmazoglu Z, et al. Effect of API-1 and FR180204 on cell proliferation and apoptosis in human DLD-1 and LoVo colorectal cancer cells[J]. Oncology Letters, 2016, 12(4): 2463-2474.
[5] Chen-Roetling J, Li Z, Chen M, et al. Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway[J]. Neuropharmacology, 2009, 56(5): 922-928.
[6] Ohori M, Takeuchi M, Maruki R, et al. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice[J]. Naunyn-Schmiedeberg's archives of pharmacology, 2007, 374(4): 311-316.
[7] Sreekanth G P, Chuncharunee A, Sirimontaporn A, et al. Role of ERK1/2 signaling in dengue virus-induced liver injury[J]. Virus research, 2014, 188: 15-26.
[8] Taglieri D M, Monasky M M, Knezevic I, et al. Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A[J]. Journal of molecular and cellular cardiology, 2011, 51(6): 988-996.
FR 180204是一种选择性的ERK抑制剂，对ERK1和ERK2的IC50值分别为0.51μM和0.33μM[1]。FR 180204可诱导TGF-β激活AP-1 (IC50=3.1µM)，并通过结合活性口袋的Q105、D106、L156和C166位点来抑制ERK活性[2]。FR 180204已被广泛用于抑制内皮细胞迁移和血管生成[3]。
在体外，FR 180204处理DLD-1细胞和LoVo细胞48小时，显著抑制了细胞活力，IC50值分别为150μM和40μM[4]。50μM的FR 180204处理小鼠胶质皮质细胞16小时，显著抑制了血红素加氧酶(HO)和乳酸脱氢酶的活性[5]。
在体内，腹腔注射100mg/kg剂量的FR 180204（每日两次），连续12天，改善了胶原诱导的小鼠关节炎，并减少了体重下降[6]。在登革热病毒(DENV)感染前1小时、感染后1小时和感染后24小时分别静脉注射50mg/kg剂量的FR 180204，显著改善了DENV诱导的Balb/c小鼠肝损伤和血液学参数[7]。连续一周每日腹腔注射100mg/kg剂量的FR 180204，显著减轻了isoproterenol (ISO)诱导的Pak-1敲除小鼠的心肌肥厚[8]。