生物活性

• 靶点

  EGFR IC50:493.8nM

  EGFR (ex19del) IC50:12.92nM

  EGFR (T790M, L858R) IC50:11.44nM

• 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. Osimertinib is an irreversible EGFR inhibitor which more potent to mutant-selective EGFR with IC50 values of 12.92 nM, 11.44 nM and 493.8 nM 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^[1]. 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^[2].
• 作用机制Osimertinib may bind to T790M EGFR kinase in the ATP-binding domain (such as T790M and C797S) ^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  PC9	0-10 μM	Function Assay	72 h	inhibits WT EGFR at low concentrations	25948633
  PC9 GR4	0-10 μM	Growth Inhibition Assay	72 h	inhibits cell growth dose dependently	25948633
  PC9 GR4	0-10 μM	Function Assay	72 h	inhibits EGFR phosphorylation and downstream signaling	25948633

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• 动物研究
  剂量	Mice (p.o.): 2.5 mg/kg[4], max = 25 mg/kg[5]
  给药途径	p.o.
  动物药代数据	Animal Dogs Dose p.o. Administration 2 mg/kg Cmax 201 nmol/L T1/2 13.1 h AUC0→t 3740 nmol·hr/L F 1.15 Tmax 2 h

• 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
  NCT02405247	-	-	Terminated(Team's request.)	-	United States, California ... more >> Research Site Oceanside, California, United States Research Site Santa Rosa, California, United States Korea, Republic of Research Site Seongnam, Gyeonggido, Korea, Republic of Research Site JinJoo, Gyeongsangnamdo, Korea, Republic of Research Site Ulsan, Ulsan Gwangyeogsi, Korea, Republic of Collapse <<
  NCT03519958	-	-	Withdrawn(The study direction ... more >>does not longer aligns the sponsor's strategy) Collapse <<	November 30, 2020	-
  NCT02368990	-	-	Withdrawn(Since the conception... more >> of the study, the competitive environment has developed and as a result this study is no longer able to generate the necessary information.) Collapse <<	June 2018	-

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• 参考文献

• [1] 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer

  [2] AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

  [3] Yosaatmadja Y, Silva S, et al. Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-544.

  [4] THE CDK4/6 INHIBITOR, G1T38, ENHANCES RESPONSE TO TARGETED THERAPIES IN PRECLINICAL MODELS OF NON-SMALL CELL LUNG CANCER

  [5] Floc'h N, Martin MJ, et al. Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions. Mol Cancer Ther. 2018 May;17(5):885-896.

  [6] Pharmacokinetics of osimertinib

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