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EPZ015666

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Chemical Structure| 1616391-65-1 同义名 : GSK3235025
CAS号 : 1616391-65-1
货号 : A272770
分子式 : C20H25N5O3
纯度 : 99%+
分子量 : 383.444
MDL号 : MFCD28411588
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(273.83 mM)，配合低频超声助溶，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：

2% DMSO+30% PEG 300+water 5 mg/mL

生物活性
靶点

  • Histone Methyltransferase

    PRMT5, Ki:5 nM
描述 The mammalian protein arginine methyltransferases are a group of nine enzymes that perform NG-mono methylation-, asymmetric-, or symmetric dimethylation of arginine residues on a range of nuclear and cytoplasmic protein substrates. Protein arginine methyltransferase-5 (PRMT5) is one member of this group which catalyzes the transfer of up to two methyl groups to arginine residues, forming ω-NG-monomethyl arginine and symmetrical ω-NG-dimethyl arginine on protein substrates[3]. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity with IC50 of 22 nM[4]. SCID mice bearing subcutaneous mantle cell lymphoma cell lines Z-138 and Maver-1 xenografts were orally given EPZ015666 on four doses: 25, 50, 100 and 200 mg/kg twice daily. Dosing at 200 mg/kg induced tumor stasis in Z-138 cells, with >93% tumor-growth inhibition (TGI) after 21 d, whereas Maver-1 cells showed >70% TGI[4]. EPZ0156660 (0 to 10 uM) dose-dependently inhibited the proliferation of multiple myeloma cell lines[5]. EPZ015666 at 5 uM also inhibited growth in patient multiple myeloma (pMM) cells cultured on a BMSCs monolayer, and also induced apoptosis of pMM cells within bone marrow mononuclear cell cultures[5]. 10 uM -EPZ treatment significantly suppressed the proliferation of several human glioblastoma cell lines: GI261, T98G, U-87 MG and A172, with loss of active S phase cells and accumulation of G2/M populations, but did not induce apoptosis[6].
作用机制 EPZ015666 binds in the peptide-binding site of PRMT5, including in the pocket occupied by the substrate arginine side chain.
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.61mL

0.52mL

0.26mL

13.04mL

2.61mL

1.30mL

26.08mL

5.22mL

2.61mL
参考文献

[1]Duncan KW, Rioux N, Boriack-Sjodin PA, Munchhof MJ, Reiter LA, Majer CR, Jin L, Johnston LD, Chan-Penebre E, Kuplast KG, Porter Scott M, Pollock RM, Waters NJ, Smith JJ, Moyer MP, Copeland RA, Chesworth R. Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. ACS Med Chem Lett. 2015 Dec 2;7(2):162-6. doi: 10.1021/acsmedchemlett.5b00380. PMID: 26985292; PMCID: PMC4753547.

[2]Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, Duncan KW. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015 Jun;11(6):432-7. doi: 10.1038/nchembio.1810. Epub 2015 Apr 27. PMID: 25915199.

[3]Gullà A, Hideshima T, Bianchi G, Fulciniti M, Kemal Samur M, Qi J, Tai YT, Harada T, Morelli E, Amodio N, Carrasco R, Tagliaferri P, Munshi NC, Tassone P, Anderson KC. Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia. 2018 Apr;32(4):996-1002. doi: 10.1038/leu.2017.334. Epub 2017 Nov 21. PMID: 29158558; PMCID: PMC5871539.

[4]Braun CJ, Stanciu M, Boutz PL, Patterson JC, Calligaris D, Higuchi F, Neupane R, Fenoglio S, Cahill DP, Wakimoto H, Agar NYR, Yaffe MB, Sharp PA, Hemann MT, Lees JA. Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma. Cancer Cell. 2017 Oct 9;32(4):411-426.e11. doi: 10.1016/j.ccell.2017.08.018. Epub 2017 Sep 28. PMID: 28966034; PMCID: PMC5929990.