N-[3-氟-4-[[6-甲氧基-7-[[3-(吗啉-4-基)丙基]氧]喹啉-4-基]氧]苯基]-N'-(4-氟苯基)环丙烷-1,1-二甲酰胺性质、用途与生产工艺
Foretinib (GSK1363089)是一种ATP竞争性的HGFR和VEGFR抑制剂，作用于Met和KDR作用最强，IC50分别为0.4 nM和0.9 nM，对Ron， Flt-1/3/4， Kit， PDGFRα/β和Tie-2作用效果稍弱，对FGFR1和EGFR几乎没有抑制活性。Phase 2。
XL880 inhibits HGF receptor family tyrosine kinases with IC50 values of 0.4 nM for Met and 3 nM for Ron. XL880 also inhibits KDR, Flt-1, and Flt-4 with IC50 values of 0.9 nM, 6.8 nM and 2.8 nM, respectively. XL880 inhibits colony growth of B16F10, A549 and HT29 cells with IC50 of 40 nM, 29 nM and 165 nM, respectively. A recent study indicates XL880 affects cell growth differently in gastric cancer cell lines MKN-45 and KATO-III. XL880 inhibits phosphorylation of MET and downstream signaling molecules in MKN-45 cells, while targets GFGR2 in KATO-III cells.
A single 100 mg/kg oral gavage dose of XL880 results in substantial inhibition of phosphorylation of B16F10 tumor Met and ligand (e.g., HGFor VEGF)-induced receptor phosphorylation of Met in liver and Flk-1/KDR in lung, which both persisted through 24 hours. Treatment with XL880 (30-100 mg/kg, once daily, oral gavage) results in reduction in tumor burden. The lung surface tumor burden is reduced by 50% and 58% following treatment with 30 and 100 mg/kg XL880, respectively. XL880 treatment of mice bearing B16F10 solid tumors also results in dose-dependent tumor growth inhibition of 64% and 87% at 30 and 100 mg/kg, respectively. For both studies, administration of XL880 is well tolerated with no significant body weight loss. XL880 is developed to target abnormal signaling of HGF through Met and simultaneously target several receptors tyrosine kinase involved in tumor angiogenesis. XL880 caused tumor hemorrhage and necrosis in human xenografts within 2 to 4 hours, and maximal tumornecrosis is observed at 96 hours (after five daily doses), resulting in complete regression.
Foretinib (GSK1363089, EXEL-2880, XL-880, GSK089) 是一种ATP竞争性的HGFR和VEGFR抑制剂，对Met (c-Met)和KDR作用最强，在无细胞试验中IC50分别为0.4 nM和0.9 nM。对Ron， Flt-1/3/4， Kit (c-Kit)， PDGFRα/β和Tie-2作用效果稍弱，对FGFR1和EGFR几乎没有抑制活性。Phase 2。
| Target | Value |
Met
(Cell-free assay)
|
0.4 nM
|
KDR
(Cell-free assay)
|
0.86 nM
|
Tie-2
(Cell-free assay)
|
1.1 nM
|
VEGFR3/FLT4
(Cell-free assay)
|
2.8 nM
|
RON
(Cell-free assay)
|
3 nM
|
XL880抑制HGF受体家族酪氨酸激酶，对Met和Ron 的IC50 值分别为0.4 nM和3 nM。XL880也会抑制KDR，Flt-1，和Flt-4，IC50值分别为0.9 nM，6.8 nM和2.8 nM。XL880抑制B16F10，A549 和HT29细胞集落生长，IC50分别为40 nM，29 nM和165 nM。一项最近的研究表明，XL880差异性影响胃癌细胞系MKN-45和KATO-III的细胞生长。XL880抑制MKN-45细胞中MET和下游信号分子的磷酸化，而在KATO-III细胞中靶向作用于GFGR2。
XL880(100 mg/kg，单一剂量，口服强喂)很大程度上抑制B16F10肿瘤Met的磷酸化和配体(比如，HGFor VEGF)诱导的肝脏中Met和肺中Flk-1/KDR受体磷酸化，两者都能持续24小时。XL880 (30-100 mg/kg，每天一次，口服强喂)处理导致肿瘤负荷减少。30和100 mg/kg XL880处理后，肺表面肿瘤负荷分别减少50%和58%。XL880处理负荷B16F10实体瘤的小鼠也会导致剂量依赖性肿瘤生长抑制，30和100 mg/kg分别导致64%和87%的抑制。对于这两项研究，XL880给药具有良好的耐受性，并且没有显著的体重损失。 XL880通过Met可以进一步以HGF的反常信号为作用靶点，同时靶向作用于几个参与肿瘤血管生成的受体酪氨酸激酶。XL880给药2到4小时后，引起人异种移植物中肿瘤出血坏死，96小时(给药5天后)观察到最大肿瘤坏死，导致完全的肿瘤消退。
N-[3-氟-4-[[6-甲氧基-7-[[3-(吗啉-4-基)丙基]氧]喹啉-4-基]氧]苯基]-N'-(4-氟苯基)环丙烷-1,1-二甲酰胺
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