生物活性

• 靶点

  EGFR (T790M, L858R) IC50:10nM

  EGFR (L858R) IC50:0.4nM

  EGFR IC50:0.5nM

• 描述EGFR (epidermal growth factor receptor) family consists of four members that belong to the ErbB lineage of proteins (ErbB1 - 4) with an external domain that binds activating ligands, such as EGF, and is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. Upon activation, EGFR phosphorylates both the receptor itself and a variety of “effector” protein. Afatinib is an irreversible inhibitor of pan-ErbB inhibitor with IC50 values of 0.4 nM, 0.5 nM, 10 nM, 14 nM and 1 nM for EGFR (L858R), EGFR (wt), EGFR (L858R/T790M), HER2^[1] (measured by cell-free in vitro kinase assays) and ErbB4^[2], respectively. Afatinib displays potent cellular effects on both EGFR and HER2 phosphorylation in cell lines with the in vitro kinase results, as well as anchorage-independent proliferation in NIH-3T3 cells ectopically expressing EGFR mutants. Afatinib inhibited survival of human NSCLC cell lines expressing HER2 776insV (NCI-H1781) or EGFR E746_A750del (HCC827), but showed no activity toward A549 cells, which expressed wild-type EGFR and HER2, but simultaneously harboring an oncogenic Kras G12S point mutation. Daily oral treatment with Afatinib at dose of 20 mg/kg for 25 days resulted in dramatic tumor regression and downregulation of EGFR and AKT phosphorylation in A431 cells xenografted models. Also the tumor regression by Afatinib can be observed in NCI-N87 cells and H1975 cells xenografted animals^[1].
• 作用机制Afatinib can form a covalent modification of the ATP-binding site in the kinase domains of EGFR (Cys 773) and HER2 (Cys 805)^[1].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22RV1	-	Growth Inhibition Assay	-	IC50=34.1754 μM	SANGER
  23132-87	-	Growth Inhibition Assay	-	IC50=0.31923 μM	SANGER
  5637	-	Growth Inhibition Assay	-	IC50=1.0151 μM	SANGER

• 更多

• 动物研究
  剂量	Mice: 20 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[4] Dose 4 mg/kg (i.v.) 8 mg/kg (p.o.) Administration i.v. p.o. Cmax 1620 nmol/L (i.v.) 397 nmol/L (p.o.) T1/2 5.22 h (i.v.) 4.54 h (p.o.) AUC0→∞ 2920 nmol·h/L (i.v.) 2600 nmol·h/L (p.o.) CL/F 55.3 ml/min·kg (i.v.) 108 ml/min·kg (p.o.) Vss/F 16.2 L/kg (i.v.) 43.6 L/kg (p.o.) AUC0→24h 2500 nmol·h/L (i.v.) 2540 nmol·h/L (p.o.) Vz/F 25.0 L/kg (i.v.) 42.8 L/kg (p.o.) MRT 4.95 h (i.v.) 6.65 h (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02145637	NSCLC	Phase 1	Unknown	July 2016	-
  NCT01649284	-	-	-	-	-
  NCT03054038	Non-Small Cell Lung Carcinoma	Phase 1	Recruiting	March 2021	United States, California ... more >> City of Hope National Medical Center Recruiting Duarte, California, United States, 91010 Contact: Thomas Fok       tfok@coh.org    Principal Investigator: Karen Reckamp, MD          Stanford Cancer Institute Recruiting Stanford, California, United States, 94035 Contact: Jordan Preiss    650-723-1002       Principal Investigator: Sukhmani Padda, MD          United States, Tennessee Vanderbilt-Ingram Cancer Center Recruiting Nashville, Tennessee, United States, 37232 Collapse <<

• 更多
• 参考文献

• [1] Li D, Ambrogio L, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008 Aug 7;27(34):4702-11.

  [2] Ferrarotto R, Gold KA, et al. Afatinib in the treatment of head and neck squamous cell carcinoma. Expert Opin Investig Drugs. 2014 Jan;23(1):135-43.

  [3] Hu X, Shi S, et al. Blocking autophagy improves the anti-tumor activity of afatinib in lung adenocarcinoma with activating EGFR mutations in vitro and in vivo. Sci Rep. 2017 Jul 4;7(1):4559.

  [4] Pharmacokinetics of afatinib