Savolitinib is a novel triazolopyrazine-based c-Met inhibitor with IC50 values of 5nM, 3nM and 6nM for inhibition of c-Met enzyme, HGF-mediated c-Met phosphorylation and HGF-induced proliferation assay in NCI-H441 cell line, respectively. Single oral dose of 3 mg/kg Savolitinib achieved inhibition of HGF-mediated c-Met phosphorylation by 84.7% at 6h post administration in mice. Oral dose of savolitinib at 1, 2.5 and 10mg/kg once daily for 21 days dose-dependently inhibited tumor growth in U87MG subcutaneous xenograft athymic nude mice model[1]. The MET D1228 site is important for Savolitinib, for the MET D1228V mutation could induce resistance to type I MET inhibitor like savolitinib[2].
作用机制
Savolitinib can bind to c-Met in a unique mode including wrapping around Met1211 c-Met in a“U-shaped” conformation. It also binds to the activation loop through Asp1228 and Lys1110 residues.[1][2]
Savolitinib/赛沃替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
OE33
1, 10, 100 nM
24 hours
To evaluate the inhibitory effects of Savolitinib on MET and downstream signaling molecules
Int J Mol Sci. 2024 May 29;25(11):5975.
MKN-45
1, 10, 100 nM
24 hours
To evaluate the inhibitory effects of Savolitinib on MET and downstream signaling molecules
Int J Mol Sci. 2024 May 29;25(11):5975.
PC9 cells
1 µM
72 hours
To evaluate the sensitivity of TPR-METWT and TPR-METD1228V to Gefitinib in combination with Savolitinib or Cabozantinib
Cancer Discov. 2016 Dec;6(12):1334-1341.
Savolitinib/赛沃替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
EGFR mutation-positive, MET-amplified NSCLC PDX model
Oral
0.3-15 mg/kg
Once daily for 20 days
To evaluate the antitumor activity of Savolitinib in combination with Osimertinib. Results showed that Savolitinib monotherapy at 15 mg/kg demonstrated significant antitumor activity (84% TGI), while combination therapy showed dose-dependent antitumor activity ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg).
Mol Cancer Ther. 2023 May 4;22(5):679-690
Mice
Lung cancer model with EGFR mutation and MET gene amplification
Oral
15 mg/kg
Once daily for 28 days
To evaluate the antitumor activity of savolitinib in combination with osimertinib, showing a tumor inhibition rate of 84%
Transl Lung Cancer Res. 2024 Jun 30;13(6):1426-1431
Mice
Patient-derived xenograft (PDX) model of NSCLC brain metastases
Oral gavage
2.5 mg/kg
Twice daily for 2 weeks
To evaluate the therapeutic effect of Savolitinib on MET exon 14 mutated NSCLC PDX model, results showed that Savolitinib significantly inhibited tumor growth and enhanced radiation response when combined with radiotherapy.
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