"目录号: HY-14721
Protein Tyrosine Kinase/RTKAutophagy-
EMD 1214063是高活性c-Met选择性抑制剂，IC50为4 nM，比对IRAK4，TrkA，Axl，IRAK1和Mer的抑制性高200倍以上。
c-Met/HGFRAutophagy
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生物活性
Description
EMD 1214063 is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. IC50 Value: 4 nM [1]Target: c-Metin vitro: EMD 1214063 inhibits HGF-induced c-Met phosphorylation in A549 cells with IC50 of 6 nM. Treatment with EMD 1214063 induces a marked reduction of c-Met–constitutive phosphorylation in EBC-1 cells with IC50 of 9 nM. EMD 1214063 effectively blocka phosphorylation of the major downstream effectors of the c-Met enzyme, such as Grb2, Gab1, Sos, PLCγ, and phosphoinositide 3-kinase, in EBC-1, MKN-45, and Hs746T cells in the range of 1 to 10 nM. EMD 1214063 considerably inhibits the viability of MKN-45 cells with IC50 of less than 1 nM. Treatment with EMD 1214063 (as low as 0.1 nM) inhibits HGF-induced NCI-H441 cell migration, whereas concentrations of 100 nM to 1 μM almost completely prevents it.in vivo: EMD 1214063 treatment, at doses of 10 mg/kg or more, results in more than 90% inhibition of c-Met phosphorylation in Hs746T xenograft tumor for a period of at least 72 hours. EMD 1214063 induces more than 50% reduction of cyclin D1 expression, which persists after 96 hours upon treatment with doses of 100 mg/kg. A transient induction of p27 and cleaved caspase-3 are also observed upon treatment with EMD 1214063. EMD 1214063 (15 mg/kg, daily) treatment induces complete regression of gastric carcinoma xenografts Hs746T, in which c-Met is amplified, overexpressed, and activated in a ligand-independent fashion.
Clinical Trial
NCT02864992
EMD Serono Research & Development Institute, Inc.-Merck KGaA-EMD Serono
Advanced (Stage IIIB/IV) Non-small Cell Lung Cancer With MET Exon 14 (METex14) Skipping Alterations
September 13, 2016
Phase 2
NCT03021642
Merck KGaA
Healthy
January 2016
Phase 1
NCT01982955
Merck KGaA
Non-small Cell Lung Cancer
December 23, 2013
Phase 1-Phase 2
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References
[1].Bladt F, et al. EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors. Clin Cancer Res, 2013, 19(11), 2941-2951.