Hepatocyte growth factor (HGF) receptor, c-Met, is the prototypic member of a family of receptor tyrosine kinases unique to deuterostomes and has emerged as an important target for the development of novel cancer therapeutics. SGX523 is a novel, ATP-competitive and selective c-Met inhibitor with an IC50 of 4 nM and a Ki of 2.7 nM. In the gastric cancer cell line GTL16, c-Met gene amplification led to constitutive signaling, which was abolished by SGX523 with an IC50 of 0.04 μM. SGX523 also abrogated HGF induced signaling in A549 lung cancer cells with an IC50 of 0.012 μM for the inhibition of c-Met autophosphorylation. Further, SGX523 inhibited the growth of gastric and lung cancer cell lines with amplification of the c-Met gene. In vivo, SGX523 significantly retarded the growth of preestablished GTL16 tumors when administered orally at doses of ≥10 mg/kg twice daily. Moreover, SGX523 (10 mg/kg; twice daily) potently inhibited U87MG tumor growth; SGX523 (30 mg/kg; twice daily) led to clear regression of U87MG tumors[3].
作用机制
SGX-523 binds to the ATP site of an inactive conformation[3].
SGX-523 细胞实验
Cell Line
Concentration
Treated Time
Description
References
H1975WT cells
5μM
24 h
The same was not seen in H1975WT cells.
PLoS One. 2017 Jan 31;12(1):e0170798.
H1975L858R cells
5μM
24 h
SGX523 only reduced stroma formation in H1975L858R.
SGX523 significantly reduced H1975L858R/T790M cell proliferation and decreased ERK phosphorylation.
PLoS One. 2017 Jan 31;12(1):e0170798.
H1975WT cells
5μM
24 h
To assess the effect of SGX-523 on cell proliferation, results showed that SGX-523 had no significant effect on the proliferation of H1975WT cells.
PLoS One. 2017 Jan 31;12(1):e0170798.
H1975L858R cells
5μM
24 h
To assess the effect of SGX-523 on cell proliferation, results showed that SGX-523 had no significant effect on the proliferation of H1975L858R cells.
PLoS One. 2017 Jan 31;12(1):e0170798.
H1975L858R/T790M cells
5μM
24 h
To assess the effect of SGX-523 on cell proliferation, results showed that SGX-523 significantly reduced the proliferation of H1975L858R/T790M cells.
PLoS One. 2017 Jan 31;12(1):e0170798.
SGX-523 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Partial hepatectomy model
Oral gavage
25 mg/kg
Starting on the operative day and continued until the time of animal sacrifice
To investigate the inhibitory effect of SGX-523 on c-Met and its impact on liver regeneration. Results showed that SGX-523 significantly reduced phosphorylation of c-Met and attenuated GW9662-induced liver regeneration and hepatocyte proliferation.
Sci Rep. 2018 Aug 8;8(1):11894
BALB/c nude mice
Xenograft model using the H1975-derived mutant cell lines
Oral gavage
60mg/kg
Daily for 12 days
SGX523 significantly reduced H1975L858R/T790M-derived tumor growth and decreased ERK phosphorylation. In H1975L858R-derived tumors, MET-EGFR interaction was increased by SGX523. There was no significant change in FRET between MET and EGFR in xenograft tissue derived from H1975WT cells.
PLoS One. 2017 Jan 31;12(1):e0170798.
BALB/c mice
Xenograft model derived from H1975L858R/T790M, H1975L858R, and H1975WT cells
Oral gavage
60mg/kg
Daily for 12 days
To assess the effect of SGX-523 on tumor growth, results showed that SGX-523 significantly inhibited tumor growth in H1975L858R/T790M-derived tumors but had no significant effect on H1975L858R and H1975WT-derived tumors.
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