Capmatinib hydrochloride

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

卡马替尼盐酸盐是一种口服生物可利用的原癌基因 c-Met (HGFR) 抑制剂，具有潜在的抗肿瘤活性。与其他激酶相比，卡马替尼对 MET 具有高度选择性。它对以 MET 扩增、显着 MET 过表达、MET 外显子 14 跳跃突变或通过配体肝细胞生长因子 (HGF) 表达激活 MET 为特征的癌症模型具有活性。

Capmatinib hydrochloride is an orally bioavailable inhibitor of the proto-oncogene c-Met (HGFR)with potential antineoplastic activity.Capmatinib was found to be highly selective for MET over other kinases.?It was active against cancer models that are characterized by MET amplification, marked MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF)[1].In cancer models where MET is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments, for example, by the addition of apoptosis-inducing BH3 mimetics.?The combinations of capmatinib and other kinase inhibitors resulted in enhanced anticancer activity against models where MET activation co-occurred with other oncogenic drivers, for example EGFR activating mutations.

Capmatinib (INCB28060) inhibits c-MET phosphorylation with an IC50 value of approximately 1 nM and a concentration of approximately 4 nM inhibits c-MET more than 90%, which isreversible and the effect is significantly reduced in several hours after the compound is removed and completely disappeared by 48 hours.Capmatinib (INCB28060) (0-10000 nM; 72 h) inhibits the proliferation of SNU-5, S114, H441 and U-87MG.Capmatinib (INCB28060) (0.06-62.25 nM; 2h) effectively inhibits phosphorylation of c-MET as well as c-MET pathway downstream effectors such as ERK1/2, AKT, FAK, GAB1, and STAT3/5.Capmatinib (INCB28060) (0.24-63 nM; over night) prevents HGF-stimulated H441 cell migration.Capmatinib (INCB28060) (0.5-50 nM; 20 min) suppresses phosphorylation of both EGFR and HER-3 rapidly.Capmatinib (INCB28060) (0-333 nM; 24 h) induces apoptosis in SNU-5 cells. Cell Viability AssayCell Line:SNU-5, S114, H441 and U-87MG Concentration:0-10000 nM Incubation Time:72 h Result:Inhibited the cell viability of SNU-5 and S114, as well as the colony formation of H441 and U-87MG, with IC50 values of 1.2 nM, 12.4 nM, ~0.5 nM and 2 nM, respectively.Cell Migration Assay Cell Line:H441 (stimulated with 50 ng/mL recombinant human HGF for 24h)Concentration:0.24, 1, 4, 16 and 63 nM Incubation Time:Over night Result:Prevented HGF-stimulated H441 cell migration, with IC50 of approximately 2 nM, and less cell migration at 16 nM.Western Blot Analysis Cell Line:SNU-5 Concentration:0.06, 0.24, 0.98, 3.91, 15.63 and 62.25 nM Incubation Time:2 h Result:Effectively inhibited phosphorylation of c-MET as well as c-MET pathway downstream effectors such as ERK1/2, AKT, FAK, GAB1, and STAT3/5.Western Blot Analysis Cell Line:H1993 cells Concentration:0.5, 5 and 50 nM Incubation Time:20 min Result:Suppressed phosphorylation of both EGFR and HER-3 rapidly and as effectively as the compound inhibited c-MET phosphorylation in H1993 cells.Apoptosis Analysis Cell Line:SNU-5 cells Concentration:0.017, 0.15, 1.37, 12.33, 111 and 333 nM Incubation Time:24 hResult:Effectively induced DNA fragmentation.

Capmatinib (INCB28060) (1-30 mg/kg; PO, twice daily, for 2 weeks) exhibits dose-dependent inhibition of tumor growth, and shows well tolerance at all doses during the treatment periods, with no evidence of overt toxicity or weight loss in U-87MG tumor mice model.Capmatinib (INCB28060) (0.03-10 mg/kg; PO, single dosage) causes inhibition of c-MET phosphorylation in S114 tumor mice model. Animal Model:Female Balb/c nu/nu mice (inoculated subcutaneously with 5×106 U-87MG glioblastoma cells)Dosage:1, 3, 10 and 30 mg/kgAdministration:PO, twice daily, for 2 weeks Result:Exhibited dose-dependent inhibition of tumor growth with 35% and 76% at 1 and 3 mg/kg once daily; resulted in partial regressions in 6 of 10 U-87MG tumor-bearing mice at 10 mg/kg once daily; and showed well tolerance at all doses during the treatment periods, with no evidence of overt toxicity or weight loss.Animal Model:Female Balb/c nu/nu mice (inoculated subcutaneously with 4×106 S114 tumor cells)Dosage:0.03, 0.1, 0.3, 1, 3 and 10 mg/kg Administration:PO, single dosage Result:Caused approximately 50% and 90% inhibition of c-MET phosphorylation at 0.03 and 0.3 mg/kg after administration of 30 min, and inhibition of phospho-c-MET exceeded 90% after 7 hours.

INC-280 hydrochloride,INCB28060 hydrochloride,NVP-INC280

Angiogenesis

c-Met/HGFR

c-Met

Respiratory system

Carcinoma, Non-Small-Cell Lung

1865733-40-9

503.4

C23H21Cl2FN6O2?

>98% (HPLC)

In Vitro:?DMSO : 20.83 mg/mL (41.38 mM)

O=C(NC)C1=CC=C(C2=NN3C(N=C2)=NC=C3CC4=CC=C5N=CC=CC5=C4)C=C1F.[H]Cl.[H]Cl.[H]O[H]

——

(-20℃)

With Ice Pack

≥ 2 years