生物活性

• 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. EGFR T790M mutation is the most common mechanism of drug resistance. AZD9291 Mesylate is the mesylate form of AZD9291. Osimertinib is an irreversible EGFR inhibitor which more potent to mutant-selective EGFR with IC50 values of 12.92nM, 11.44nM and 493.8nM for Exon 19 deletion EGFR, L858R/T790M EGFR and WT EGFR, with a 200-fold selectivity for T790M/L858R over wild type EGFR, in LoVo cells, respectively. Osimertinib potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; <25nM) and EGFRm+/T790M (e.g. H1975; <25nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; >500nM). Consistent with that, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. Oral administration of Osimertinib once daily at dose of 5mg/kg caused profound regression of tumors across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumor models in vivo, after 14 days dosing, and this was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumors with Osimertinib led to a complete and sustained macroscopic response, with no visible tumors after 40 days dosing, and being maintained beyond 100 days.
• 作用机制Osimertinib may bind to T790M EGFR kinase in the ATP-binding domain (such as T790M and C797S).^[3]

• 动物研究
  剂量	Mice: 5 mg/kg, 10 mg/kg[1] (p.o.) Rat: 200 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Dogs[3] Dose 1 mg/kg (i.v.) 2 mg/kg (p.o.) Administration i.v. p.o. F 115% (p.o.) Vd 18.2 L/kg (i.v.) T1/2 10.3 h (i.v.) 13.1 h (p.o.) Tmax 2 h (p.o.) CL 1.28 L/h/kg (i.v.) Cmax 195 nmol/L (i.v.) 201 nmol/L (p.o.) AUC0→t 1550 nmol·h/L (i.v.) 3740 nmol·h/L (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
  NCT03050411	Nonsmall Cell Lung Cancer	Phase 1	Recruiting	October 2019	China, Beijing ... more >> Peking University Third Hospital Recruiting Beijing, Beijing, China Contact: Li Liang, MD    13241870816 Collapse <<
  NCT03460275	Non-small Cell Lung Cancer	Phase 2	Recruiting	December 2020	China, Guangdong ... more >> Sun Yat-sen University Cancer Center Recruiting GuangZhou, Guangdong, China, 510060 Contact: Hao Long, professor    +862087343314    longhao@sysucc.org.cn    Contact: Ruping Xing    +862087343736    xingrp@sysucc.org.cn    Principal Investigator: Hao Long, professor          Sun Yat sen University cancer center Recruiting Guangzhou, Guangdong, China Contact: Hao Long, prof    +86 2087343262    longhao@sysucc.org.cn    Contact: Ruping Xing    +86 2087343736    xingrp@sysucc.org.cn Collapse <<

• 参考文献

• [1] Finlay MR, Anderton M, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67.

  [2] Cross DA, Ashton SE, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.

  [3] AZD9291