S49076 is a novel and potent inhibitor of MET/MET mutations, AXL/MER, and FGFR1/2/3 with IC50 values of 1nM/1-17nM, 7nM/2nM, 18nM/17nM/15nM, respectively. S49076 potently blocked cellular phosphorylation of MET (3-10nM), AXL (10-1000nM), and FGFRs (>300nM) and inhibited downstream signaling p-FRS2 and p-ERK in vitro. S49076 inhibited viability (IC50 values were 3, 167, and >10μM for GTL-16, SNU-16, and MKN-7, respectively), motility (IC50 for inhibition of HGF-induced cell motility of 14nM in A549 cells), and three-dimensional colony formation of cancer cells expressing MET, AXL, or FGFRs. Orally administered S49076 at doses ranging in 0.78-12.5mg/kg inhibited MET signaling in subcutaneous xenografts in balb/c nu/nu mice at doses, suggesting its good pharmacodynamics. Oral administration of S49076 inhibited tumor growth in mice xenograft GTL-16, U87-MG and SNU-16 at doses ranging in 3.125-50mg/kg, 6.25-50mg/kg and 37.5-100mg/kg, respectively[2].
Evaluate the antiproliferative activity of S49076 in EGFR-TKI-resistant cells, results showed PC9-GR4-AZD2 cells were sensitive to S49076
Nat Commun. 2019 Apr 18;10(1):1812
PC9-GR1-AZD3
0.2 µM
72 hours
Evaluate the antiproliferative activity of S49076 in EGFR-TKI-resistant cells, results showed PC9-GR1-AZD3 cells were sensitive to S49076
Nat Commun. 2019 Apr 18;10(1):1812
PC9-GR1-AZD1
0.2 µM
72 hours
Evaluate the antiproliferative activity of S49076 in EGFR-TKI-resistant cells, results showed PC9-GR1-AZD1 cells were sensitive to S49076
Nat Commun. 2019 Apr 18;10(1):1812
PC9-ER
0.3 µM
72 hours
Evaluate the antiproliferative activity of S49076 in EGFR-TKI-resistant cells, results showed PC9-ER cells were sensitive to S49076
Nat Commun. 2019 Apr 18;10(1):1812
PC9-GR3
0.3 µM
72 hours
Evaluate the antiproliferative activity of S49076 in EGFR-TKI-resistant cells, results showed PC9-GR3 cells were sensitive to S49076
Nat Commun. 2019 Apr 18;10(1):1812
S49076 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
PC9-ER xenograft model
Oral
37.5 mg/kg/day
Twice daily for 3 weeks
S49076 inhibited the growth of PC9-ER xenografts in a dose-dependent manner, with a 55% reduction in tumor growth at the highest dosage of 37.5 mg/kg/day
Nat Commun. 2019 Apr 18;10(1):1812
SCID female mice
NSCLC xenograft model
Oral
17.5 mg/kg and 35 mg/kg
Twice daily for 2 weeks
To evaluate the effects of S49076 alone or in combination with gefitinib on tumor growth and host body weight. Results showed that S49076 exhibited a greater anticancer effect and a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib.
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