生物活性

• 靶点

  MEK1 IC50:0.92nM

  MEK2 IC50:1.8nM

• 描述Trametinib, also called as GSK1120212 or JTP-74057, can strongly inhibit MEK1/2 kinase activities with IC50 value of 0.92nM and 1.8nM, respectively, without inhibition on the other 98 kinases (measured by Raf-MEK-ERK cascade kinase assay) regardless of the isotype of Raf and MEK. Trametinib can inhibit constitutive ERK phosphorylation (downstream of MEK) in cell lines, while the effect on anti-proliferation differs. Among them, HT-29 and COLO205 cells with a constitutively active B-Raf mutant were most sensitive to trametinib while COLO320 DM cells bearing the wild-type gene in both B-Raf and K-Ras were found to be resistant to trametinib. Oral treatment of trametinib 1mg/kg daily for 14 days blocked the tumor increase almost completely in nude mice bearing the HT-29 xenografts^[1].Trametinib is indicated for the treatment in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations detected by an FDA-approved test^[2].
  
• 作用机制Trametinib binds to MEK1/2 and induces allosteric inhibition of MEK1/2 catalysis.^[3]

• 动物研究
  剂量	Mice: min = 0.3 mg/kg[1], max = 2 mg/kg[2]
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03225664	Lung Diseases Due to External ... more >>Agents Non-Small Cell Lung Cancer Collapse <<	Phase 1 Phase 2	Recruiting	May 2020	United States, Texas ... more >> University of Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Clinical Research Operations       CR_Study_Registration@mdanderson.org Collapse <<
  NCT02872259	Melanoma	Phase 1 Phase 2	Recruiting	March 2020	Norway ... more >> Haukeland University Hospital Recruiting Bergen, Norway, 5021 Contact: Oddbjørn Straume, MD, PhD       oddbjorn.straume@helse-bergen.no    Akershus Univerisity Hospital Not yet recruiting Lørenskog, Norway, 1478 Contact: Jürgen Geisler, MD, PhD       Jurgen.geisler@ahus.no    Oslo University Hospital, Radiumhospitalet Recruiting Oslo, Norway, 0424 Contact: Marta Nyakas, MD, PhD       marta.nyakas@ous.no    University Hospital of North Norway Recruiting Tromsø, Norway, 9038 Contact: Anita Amundsen, MD       Anita.amundsen@unn.no    St. Olavs Hospital Recruiting Trondheim, Norway, 7006 Contact: Jarle Karlsen, MD       Jarle.Karlsen@stolav.no Collapse <<
  NCT02039947	Melanoma and Brain Metastases	Phase 2	Completed	-	-

• 更多
• 参考文献

• [1] Fujishita T, Kajino-Sakamoto R, et al. Antitumor activity of the MEK inhibitor trametinib on intestinal polyp formation in Apc(Δ716) mice involves stromal COX-2. Cancer Sci. 2015 Jun;106(6):692-9.

  [2] Kawaguchi K, Igarashi K, et al. MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX). Oncotarget. 2017 Jul 18;8(29):47490-47496.

  [3] Walters DM, Lindberg JM, et al. Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib. Neoplasia. 2013;15(2):143-55.

  [4] Ganesh S, Shui X, et al. β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models. Mol Cancer Ther. 2018;17(2):544-553.