生物活性

• 描述Epidermal growth factor receptor (EGFR) is a transmembrane protein involved in cell differentiation and proliferation upon the activation through the binding of its specific ligands. Osimertinib is a potent, irreversible inhibitor of EGFR-sensitizing and T790M-resistant mutation^[4]. AZ5104 is an active, demethylated metabolite of osimertinib, which shows the inhibition activity for EGFR (L858R/T790M), EGFR (L858R), EGFR (L861Q), and EGFR (wildtype) with IC50 values of < 1 nM, 6 nM, 1 nM and 25 nM, respectively. AZ5104 had greater potency against wild-type EGFR (33 nM in LOVO), ex19del (2 nM in PC-9), and T790M (2 nM in H1975) cell lines. AZ5104 treatment in HEK293 cells also showed more potency than osimertinib against phosphorylated HER2. In MCF10A cells stably expressing HER2^L869R/T798I, cell growth was significantly blocked after the treatment of 100 nM AZ5104 for 5 days. Treatment of 100 nM AZ5104 for 4 hours in serum-free media inhibited pAKT, pERK, and pS6 in both BT474^GFP and BT474^HER2-T798M cells^[5]. Compared to vehicle-treated mice, administration of AZ5104 (5 mg/kg/day) for one to two weeks effectively reduced the tumor volume in both C/L858R and C/L+T mice^[6].
• 作用机制AZ5104 is the active metabolite of osimertinib, which targets the sensitizing and T790M resistant mutant forms of the EGFR. It binds to EGFR through targeting the cysteine-797 residue in the ATP binding site by covalent bond formation, thereby inhibiting the activity of EGFR^[6].

• 动物研究
  剂量	Mice: 50 mg/kg[3] (p.o.)
  给药途径	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
  NCT03255083	Non-small Cell Lung Cancer (NS... more >>CLC) Collapse <<	Phase 1	Recruiting	October 15, 2020	United States, Massachusetts ... more >> Dana-Farber Cancer Institute Withdrawn Boston, Massachusetts, United States, 02215 United States, New York Memorial Sloan Kettering Cancer Center Withdrawn New York, New York, United States, 10065 France CHU de Grenoble - Hôpital Albert Michallon Recruiting Grenoble, France, 38043 Contact: Principal Investigator    +33 476768708    Dmoro.pneumo@chu-grenoble.fr    Hôpital de la Timone Withdrawn Marseille, France, 13005 Institut Gustave Roussy Withdrawn Villejuif, France, 94800 Taiwan Taipei Medical University, Shuang Ho Hospital Not yet recruiting New Taipei City, Taiwan, 235 China Medical University Hospital Not yet recruiting Taichung, Taiwan, 404 Taichung Veterans General Hospital Not yet recruiting Taichung, Taiwan, 40705 National Cheng-Kung University Hospital Not yet recruiting Tainan, Taiwan, 704 National Taiwan University Hospital Not yet recruiting Taipei, Taiwan, 100 Taipei Medical University Hospital Not yet recruiting Taipei, Taiwan, 110 Taipei Veterans General Hospital Not yet recruiting Taipei, Taiwan, 11217 Collapse <<
  NCT02511106	Stage IB-IIIA Non-small Cell L... more >>ung Carcinoma Collapse <<	Phase 3	Recruiting	January 31, 2022	-
  NCT03732352	EGFR Gene Amplification ... more >> EGFR Gene Mutation Glioblastoma Recurrent Glioblastoma Supratentorial Glioblastoma TP53 wt Allele Collapse <<	Phase 2	Not yet recruiting	November 1, 2021	United States, California ... more >> UCLA / Jonsson Comprehensive Cancer Center Not yet recruiting Los Angeles, California, United States, 90095 Contact: Timothy F. Cloughesy    310-825-5321    tcloughesy@mednet.ucla.edu    Principal Investigator: Timothy F. Cloughesy Collapse <<

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• 参考文献

• [1] Yates JW, Ashton S, et al. Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic-Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104. Mol Cancer Ther. 2016 Oct;15(10):2378-2387.

  [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] 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.

  [4] Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DA, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL. 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.

  [5] Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE Jr, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL. An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer. Cancer Discov. 2017 Jun;7(6):575-585. doi: 10.1158/2159-8290.CD-16-1431. Epub 2017 Mar 8. Erratum in: Cancer Discov. 2019 Feb;9(2):303.

  [6] Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.

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