849217-64-7
中文名稱
N-[3-氟-4-[[6-甲氧基-7-[[3-(嗎啉-4-基)丙基]氧]喹啉-4-基]氧]苯基]-N'-(4-氟苯基)環(huán)丙烷-1,1-二甲酰胺
英文名稱
Foretinib (GSK1363089)
CAS
849217-64-7
分子式
C34H34F2N4O6
分子量
632.654
MOL 文件
849217-64-7.mol
更新日期
2024/12/18 10:09:05
849217-64-7 結構式
基本信息
中文別名
GSK1363089FORETINIB
EXEL-2880
(試劑)FORETINIB (GSK1363089, XL880)
N-[3-氟-4-[[6-甲氧基-7-[[3-(嗎啉-4-基)丙基]氧]喹啉-4-基]氧]苯基]-N'-(4-氟苯基)環(huán)丙烷-1,1-二甲酰胺
FORETINIB GLAXOSMITHKLINE PAPILLARY RENAL CELL CARCINOMA PHASE IIRSCH. TRIANGLE PARK, NC (SEE ALSO HEAD/NECK) (888) 825-5249
英文別名
XL880GSK089
Foretinib
EXEL-2880
GSK 1363089
EXEL-2880/XL-880
XL-880,Foretinib
Foretinib, >=98%
XL880(GSK1363089)
Foretinib (XL-880)
所屬類別
生物化工：蛋白酪氨酸激酶物理化學性質
熔點>98°C (dec.)
沸點828.5±65.0 °C(Predicted)
密度1.372
儲存條件Sealed in dry,Store in freezer, under -20°C
溶解度DMSO（微溶）、乙醇（微溶）
酸度系數(shù)(pKa)13.14±0.70(Predicted)
形態(tài)黃色粉末
顏色淡黃色至黃色
CAS 數(shù)據(jù)庫849217-64-7
常見問題列表
生物活性
Foretinib (GSK1363089)是一種ATP競爭性的HGFR和VEGFR抑制劑，作用于Met和KDR作用最強，IC50分別為0.4 nM和0.9 nM，對Ron， Flt-1/3/4， Kit， PDGFRα/β和Tie-2作用效果稍弱，對FGFR1和EGFR幾乎沒有抑制活性。Phase 2。體外研究
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.體內(nèi)研究
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.生物活性
Foretinib (GSK1363089, EXEL-2880, XL-880, GSK089) 是一種ATP競爭性的HGFR和VEGFR抑制劑，對Met (c-Met)和KDR作用最強，在無細胞試驗中IC50分別為0.4 nM和0.9 nM。對Ron， Flt-1/3/4， Kit (c-Kit)， PDGFRα/β和Tie-2作用效果稍弱，對FGFR1和EGFR幾乎沒有抑制活性。Phase 2。靶點
| 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 |
體外研究
XL880抑制HGF受體家族酪氨酸激酶，對Met和Ron 的IC50 值分別為0.4 nM和3 nM。XL880也會抑制KDR，F(xiàn)lt-1，和Flt-4，IC50值分別為0.9 nM，6.8 nM和2.8 nM。XL880抑制B16F10，A549 和HT29細胞集落生長，IC50分別為40 nM，29 nM和165 nM。一項最近的研究表明，XL880差異性影響胃癌細胞系MKN-45和KATO-III的細胞生長。XL880抑制MKN-45細胞中MET和下游信號分子的磷酸化，而在KATO-III細胞中靶向作用于GFGR2。
體內(nèi)研究
XL880(100 mg/kg，單一劑量，口服強喂)很大程度上抑制B16F10腫瘤Met的磷酸化和配體(比如，HGFor VEGF)誘導的肝臟中Met和肺中Flk-1/KDR受體磷酸化，兩者都能持續(xù)24小時。XL880 (30-100 mg/kg，每天一次，口服強喂)處理導致腫瘤負荷減少。30和100 mg/kg XL880處理后，肺表面腫瘤負荷分別減少50%和58%。XL880處理負荷B16F10實體瘤的小鼠也會導致劑量依賴性腫瘤生長抑制，30和100 mg/kg分別導致64%和87%的抑制。對于這兩項研究，XL880給藥具有良好的耐受性，并且沒有顯著的體重損失。 XL880通過Met可以進一步以HGF的反常信號為作用靶點，同時靶向作用于幾個參與腫瘤血管生成的受體酪氨酸激酶。XL880給藥2到4小時后，引起人異種移植物中腫瘤出血壞死，96小時(給藥5天后)觀察到最大腫瘤壞死，導致完全的腫瘤消退。