| CAS |
No.1415560-69-8 |
| 英文名称 |
PF-02341066 Hydrochloride |
| 别名 |
;CS-1156;Crizotinibhydrochloride; |
| 分子式 |
C21H23Cl3FN5O |
| 分子量 |
486.8 |
| 溶解性 |
Soluble in DMSO ≥5mg/mL(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| MDL |
MFCD23378578 |
| SMILES |
C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N.Cl |
| InChIKey |
BTDNHKQCPIBABF-UTONKHPSSA-N |
| InChI |
InChI=1S/C21H22Cl2FN5O.ClH/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15;/h2-3，8-12，15，26H，4-7H2，1H3，(H2，25，27);1H/t12-;/m1./s1 |
| PubChem CID |
71576688 |
| 靶点 |
c-Met;ALK;ROS1 |
| 通路 |
Protein Tyrosine Kinase/RTK |
| 背景说明 |
PF-02341066 Hydrochloride是具有选择性的 ATP 竞争性双 ALK 和 c-Met 抑制剂。也是 ROS 原癌基因 1 (ROS1) 抑制剂，具有有效的肿瘤生长抑制作用。 |
| 生物活性 |
Crizotinib hydrochloride (PF-02341066 hydrochloride) is an orally bioavailable， selective， and ATP-competitive dual ALK and c-Met inhibitor with IC50s of 20 and 8 nM， respectively. Crizotinib hydrochloride (PF-02341066 hydrochloride) inhibits tyrosine phosphorylation of NPM-ALK and tyrosine phosphorylation of c-Met with IC50s of 24 and 11 nM in cell-based assays， respectively. It is also a ROS proto-oncogene 1 (ROS1) inhibitor. Crizotinib hydrochloride (PF-02341066 hydrochloride) has effective tumor growth inhibition.[1-4] |
| IC50 |
IC50: 20 nM (ALK)， 8 nM (c-Met)[3] |
| In Vitro |
PF-2341066 displays similar potency against c-Met phosphorylation in mIMCD3 mouse or MDCK canine epithelial cells with IC50 of 5 nM and 20 nM， respectivly. PF-2341066 shows improved or similar activity against NIH3T3 cells engineered to express c-Met ATP-binding site mutants V1092I or H1094R or the P-loop mutant M1250T with IC50 of 19 nM， 2 nM and 15 nM， respectively， compared with NIH3T3 cells expressing wild-type receptor with IC50 of 13 nM. In contrast， a marked shift in potency of PF-2341066 is observed against cells engineered to express c-Met activation loop mutants Y1230C and Y1235D with IC50 of 127 nM and 92 nM， respectively， compared with wild-type receptor. PF-2341066 also potently prevents the phosphorylation of c-Met in NCI-H69 and HOP92 cells， with IC50 of 13 nM and 16 nM， respectively， which express the endogenous c-Met variants R988C and T1010I， respectively[1].
PF-2341066 also potently inhibits NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells with an IC50 of 24 nM. PF-2341066 potently prevents cell proliferation， which is associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells with IC50 of 30 nM， but not ALK-negative lymphoma cells[2]. |
| In Vivo |
PF-2341066 reveals the ability to cause marked regression of large established tumors (> 600 mm3) in both the 50 mg/kg/day and 75 mg/kg/day treatment cohorts， with a 60% decrease in mean tumor volume over the 43-day administration schedule in the GTL-16 model. In an another study， PF-2341066 displays the ability to completely inhibits GTL-16 tumor growth for >3 months， with only 1 of 12 mice exhibiting a significant increase in tumor growth over the 3-month treatment schedule at 50 mg/kg/day. A significant dose-dependent reduction of CD31-positive endothelial cells is observed at 12.5 mg/kg/day， 25 mg/kg/day， and 50 mg/kg/day in GTL-16 tumors， indicating that inhibition of MVD shows a dose-dependent correlation to antitumor efficacy. PF-2341066 displays a significant dose-dependent reduction of human VEGFA and IL-8 plasma levels in both the GTL-16 and U87MG models. Marked inhibition of phosphorylated c-Met， Akt， Erk， PLCλ1， and STAT5 levels is observed in GTL-16 tumors following p.o. administration of PF-2341066[1].
Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg PF-2341066 elicits tumor regression that is associated with a slow reduction in 18F-FDG uptake and decreases expression of the glucose transporter 1， GLUT-1[4]. |
| 细胞实验 |
Tumor cells are seeded in 96-well plates at low density in media supplemented with 10% FBS (growth media) and transferred to serum-free media (0% FBS and 0.04% BSA) after 24 h. Appropriate controls or designated concentrations of PF-2341066 are added to each well， and cells are incubated for 24 to 72 h. Human umbilical vascular endothelial cells (HUVEC) are seeded in 96-well plates in EGM2 media for 5 to 6 h at > 20，000 cells per well and transferred to serum-free media overnight. The following day， appropriate controls or designated concentrations of PF-2341066 are added to each well， and after 1 h incubation， HGF is added to designated wells at 100 ng/mL. A 3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium bromide assay is done to determine the relative tumor cell or HUVEC numbers.[1-4] |
| 动物实验 |
Athymic mice bearing xenografts (300-800 mm3) are given PF-2341066 in water by oral gavage at designated dose levels. At designated times following PF-2341066 administration， mice are humanely euthanized， and tumors are resected. Tumors are snap frozen and pulverized using a liquid nitrogen-cooled cryomortar and pestle， protein lysates are generated， and protein concentrations are determined using a BSA assay. The level of total and phosphorylated protein is determined using a capture ELISA or immunoprecipitation-immunoblotting method.[1-4] |
| 数据来源文献 |
[1]. Zou HY， et al. An orally available small-molecule inhibitor of c-Met， PF-2341066， exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007， 67(9)， 4408-4417.
[2]. Christensen JG， et al. Cytoreductive antitumor activity of PF-2341066， a novel inhibitor of anaplastic lymphoma kinase and c-Met， in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007， 6(12 Pt 1)， 3314-3322.
[3]. Cui JJ， et al. Structure based drug design of crizotinib (PF-02341066)， a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63.
[4]. Cullinane C， et al. Differential (18)F-FDG and 3-deoxy-3-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models. J Nucl Med. 2011 Aug;52(8):1261-7 |
| 规格 |
5mg 10mg 25mg 50mg 100mg 200mg 500mg |
| 单位 |
瓶 |
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英语
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