| CAS |
No.848942-61-0 |
| 中文名称 |
沙普替尼 |
| 英文名称 |
Sapitinib |
| 别名 |
AZD-8931 |
| 分子式 |
C23H25ClFN5O3 |
| 分子量 |
473.93 |
| 溶解性 |
Soluble in DMSO ≥3mg/mL(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
White to off-white Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| 运输条件 |
冷藏运输 |
| MDL |
MFCD18385011 |
| SMILES |
CNC(=O)CN1CCC(CC1)OC2=C(C=C3C(=C2)C(=NC=N3)NC4=C(C(=CC=C4)Cl)F)OC |
| InChIKey |
DFJSJLGUIXFDJP-UHFFFAOYSA-N |
| InChI |
InChI=1S/C23H25ClFN5O3/c1-26-21(31)12-30-8-6-14(7-9-30)33-20-10-15-18(11-19(20)32-2)27-13-28-23(15)29-17-5-3-4-16(24)22(17)25/h3-5，10-11，13-14H，6-9，12H2，1-2H3，(H，26，31)(H，27，28，29) |
| PubChem CID |
11488320 |
| 靶点 |
EGFR |
| 通路 |
Angiogenesis;Protein Tyrosine Kinase/RTK |
| 背景说明 |
Sapitinib是一种可逆的，ATP竞争性EGFR，ErbB2和ErbB3抑制剂。 |
| 生物活性 |
Sapitinib (AZD-8931) is a reversible， ATP competitive EGFR inhibitor of with IC50s of 4， 3 and 4 nM for EGFR， ErbB2 and ErbB3 in cells， respectively.[1-4] |
| In Vitro |
AZD8931 shows potent inhibitory effect on erbB2 in the ligand-independent MCF-7 cl24 cells， with IC50 of 59 nM[1]. AZD8931 (1 μM) has no significant effect on EGFR expression level， but significantly inhibits phosphorylation of Akt in a time- and dose-dependent manner in both SUM149 and FC-IBC-02 cells. AZD8931 (0.01， 0.1， 1， or 2 μM) inhibits proliferation and induces apoptosis in human IBC cells[2]. At the cellular level， AZD8931 inhibits EGF-stimulated phosphorylation of EGFR in the KB cell line (IC50: 4 nM) and heregulin-stimulated phosphorylation of HER2 (IC50: 3 nM) and HER3 (IC50: 4 nM) in the MCF-7 cell line. However， AZD8931 exhibits no CYP P450 inhibition (IC50 > 10 μM against 1A2， 2C9， 2C19， 2D6， and 3A4)[3]. |
| In Vivo |
AZD8931 (6.25-50 mg/kg， p.o.) significantly inhibits BT474c (breast)， Calu-3 (NSCLC)， LoVo (colorectal)， FaDu (SCCHN)， and PC-9 (NSCLC) tumor xenograft growth. AZD8931 is active in xenograft tumor models responsive to EGFR inhibition alone (LoVo and PC-9) or EGFR or erbB2 inhibition (BT474c， Calu-3， and FaDu). AZD8931 causes pharmacodynamic changes in proliferation and apoptosis markers in human tumor xenograft models[1]. AZD8931 (25 mg/kg， p.o.) significantly inhibits the growth of SUM149 and FC-IBC-02 cells in vivo in SCID mice[2]. AZD8931 displays favorable oral pharmacokinetics in rat and dog (low clearance and good bioavailability) and low human hepatocyte turnover (Clint [3]. |
| 细胞实验 |
Cells are incubated for 96 h with a suitable range of concentrations of drug to ensure accurate estimation of the inhibitor concentration required to give 50% growth inhibition (GI50; typically between 0.001-10 μM). Viable cell number is determined by 4 h of incubation with MTS Colorimetric Assay reagent and absorbance measured at 490 nm on a spectrophotometer. Each experiment is carried out in triplicate for each drug concentration and data are presented as geometric means. Sensitivity groupings of GI50 data are 7 μM. |
| 动物实验 |
Swiss nude (nu/nu genotype) and severe combined immunodeficient mice are used. AZD8931， GW572016， and ZD1839 are suspended in a 1% (v/v) solution of polyoxyethylenesorbitan monooleate (Tween 80) in deionized water. Animals are given AZD8931 (6.25-50 mg/kg)， GW572016 (100 mg/kg)， ZD1839 (100-150 mg/kg)， or vehicle control once (qd) or twice daily (bid) by oral gavage. The duration of each study is determined by tumor growth characteristics， with studies ending once tumors reach ~1 cm3. Tumor volume and percentage tumor growth inhibition are calculated and statistical analysis of any change in tumor volume is carried out using a standard t test (P value of lower then 0.05 is considered to be statistically significant). |
| 数据来源文献 |
[1]. Hickinson DM， et al. AZD8931， an equipotent， reversible inhibitor of signaling by epidermal growth factor receptor， ERBB2 (HER2)， and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer. Clin Cancer Res. 2010 Feb 15;16(4):1159-69.
[2]. Mu Z， et al. AZD8931， an equipotent， reversible inhibitor of signaling by epidermal growth factor receptor (EGFR)， HER2， and HER3: preclinical activity in HER2 non-amplified inflammatory breast cancer models. J Exp Clin Cancer Res. 2014 May 30;33:47.
[3]. Barlaam B， et al. Discovery of AZD8931， an Equipotent， Reversible Inhibitor of Signaling by EGFR， HER2， and HER3 Receptors. ACS Med Chem Lett. 2013 May 31;4(8):742-6.
[4]. Wang R， et al. Endothelial Cells Promote Colorectal Cancer Cell Survival by Activating the HER3-AKT Pathway in a Paracrine Fashion. Mol Cancer Res. 2018 Aug 21. pii: molcanres.0341.2018. |
| 规格 |
1mg 5mg 10mg 25mg 50mg 100mg |
| 单位 |
瓶 |
中文
英语
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