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AZ-5104

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Chemical Structure| 1421373-98-9 同义名 : -
CAS号 : 1421373-98-9
货号 : A557620
分子式 : C27H31N7O2
纯度 : 99%+
分子量 : 485.581
MDL号 : MFCD28899992
存储条件：

粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(61.78 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

1% Tween 80+water 30 mg/mL suspension

生物活性
靶点

  • EGFR/ErbB1

    EGFR (L858R), IC50:6 nM

    EGFR (L861Q) , IC50:<1 nM

  • ErbB4

    ErbB4, IC50:7 nM
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 HER2L869R/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 BT474GFP and BT474HER2-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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.06mL

0.41mL

0.21mL

10.30mL

2.06mL

1.03mL

20.59mL

4.12mL

2.06mL
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.