MS4078 is a PROTAC targeting on ALK with DC50 value of 11nM, consist of ALK inhibitor ceritinib as a warhead linked to CRBN ligand Pomalidomide. Treatment with MS4078 led a degradation of both ALK fusion protein, including NPM-ALK of SU-DHL-1 cells and EML4-ALK of NCI-H2228 cells, as well as downregulation of ALK auto phosphorylation and down-steam STAT3 phosphorylation, in both cell lines in a dose-dependent manner at concentration ranging in 3-100nM for 16h and in a time-dependent manner at concentration of 30nM for SU-DHL-1 cells or 60nM for NCI-H2228 cells within 24h. MS4078 exhibited potent antiproliferation against SU-DHL-1 cells with IC50 value of 33nM post 3 days. MS4078 is available in mice through intraperitoneal administration with highest plasma concentration 3,000nM achieved at 2 h at dose of 50mg/kg. MS4748 and MS4740 work as the negative controls for MS4078[1].
MS4078 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NCI-H2228 lung cancer cells
34-100 nM
16 hours
MS4078 significantly reduced EML4-ALK protein levels and inhibited ALK auto-phosphorylation in NCI-H2228 cells.
Eur J Med Chem. 2018 May 10;151:304-314
SU-DHL-1 lymphoma cells
3-100 nM
16 hours
MS4078 significantly decreased cellular levels of oncogenic active ALK fusion proteins and inhibited ALK auto-phosphorylation and downstream STAT3 phosphorylation in SU-DHL-1 cells.
Eur J Med Chem. 2018 May 10;151:304-314
MS4078 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Intraperitoneal injection
50 mg/kg
Single dose, over 12 hours
Evaluated the pharmacokinetic properties of MS4078 in mice, showing good plasma exposure.
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