EPZ015666 - CAS 1616391-65-1
Catalog number: B0084-463445
Category: Inhibitor
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Molecular Formula:
C20H25N5O3
Molecular Weight:
383.44
COA:
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Targets:
HMTase
Description:
EPZ015666 shows potent cellular activity that blocks symmetric dimethylation of SmD3 and inhibit proliferation of MCL cell lines (Z-138, Granta-519, Maver-1, Mino, and Jeko-1) with IC50 of 96-904 nM.
Ordering Information
Catalog Number Size Price Stock Quantity
B0084-463445 300 mg $299 In stock
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Purity:
>98%
Synonyms:
EPZ015666; EPZ-015666; EPZ 015666; GSK3235025; GSK-3235025; GSK 3235025.
MSDS:
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InChIKey:
ZKXZLIFRWWKZRY-KRWDZBQOSA-N
InChI:
InChI=1S/C20H25N5O3/c26-17(10-25-6-5-14-3-1-2-4-15(14)9-25)8-21-20(27)18-7-19(23-13-22-18)24-16-11-28-12-16/h1-4,7,13,16-17,26H,5-6,8-12H2,(H,21,27)(H,22,23,24)/t17-/m0/s1
Canonical SMILES:
C1CN(CC2=CC=CC=C21)CC(CNC(=O)C3=CC(=NC=N3)NC4COC4)O
1.Species differences in metabolism of EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5) inhibitor.
Rioux N1, Duncan KW, Lantz RJ, Miao X, Chan-Penebre E, Moyer MP, Munchhof MJ, Copeland RA, Chesworth R, Waters NJ. Xenobiotica. 2015 Jul 31:1-10. [Epub ahead of print]
1. Metabolite profiling and identification studies were conducted to understand the cross-species differences in the metabolic clearance of EPZ015666, a first-in-class protein arginine methyltransferase-5 (PRMT5) inhibitor, with anti-proliferative effects in preclinical models of Mantle Cell Lymphoma. EPZ015666 exhibited low clearance in human, mouse and rat liver microsomes, in part by introduction of a 3-substituted oxetane ring on the molecule. In contrast, a higher clearance was observed in dog liver microsomes (DLM) that translated to a higher in vivo clearance in dog compared with rodent. 2. Structure elucidation via high resolution, accurate mass LC-MSn revealed that the prominent metabolites of EPZ015666 were present in hepatocytes from all species, with the highest turnover rate in dogs. M1 and M2 resulted from oxidative oxetane ring scission, whereas M3 resulted from loss of the oxetane ring via an N-dealkylation reaction. 3. The formation of M1 and M2 in DLM was significantly abrogated in the presence of the specific CYP2D inhibitor, quinidine, and to a lesser extent by the CYP3A inhibitor, ketoconazole, corroborating data from human recombinant isozymes.
2.Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.
Duncan KW1, Rioux N1, Boriack-Sjodin PA1, Munchhof MJ1, Reiter LA1, Majer CR1, Jin L1, Johnston LD1, Chan-Penebre E1, Kuplast KG1, Porter Scott M1, Pollock RM1, Waters NJ1, Smith JJ1, Moyer MP1, Copeland RA1, Chesworth R1. ACS Med Chem Lett. 2015 Dec 2;7(2):162-6. doi: 10.1021/acsmedchemlett.5b00380. eCollection 2016.
The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).
3.Species differences in metabolism of EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5) inhibitor.
Rioux N1, Duncan KW, Lantz RJ, Miao X, Chan-Penebre E, Moyer MP, Munchhof MJ, Copeland RA, Chesworth R, Waters NJ. Xenobiotica. 2015 Aug 21:1-10. [Epub ahead of print]
1. Metabolite profiling and identification studies were conducted to understand the cross-species differences in the metabolic clearance of EPZ015666, a first-in-class protein arginine methyltransferase-5 (PRMT5) inhibitor, with anti-proliferative effects in preclinical models of Mantle Cell Lymphoma. EPZ015666 exhibited low clearance in human, mouse and rat liver microsomes, in part by introduction of a 3-substituted oxetane ring on the molecule. In contrast, a higher clearance was observed in dog liver microsomes (DLM) that translated to a higher in vivo clearance in dog compared with rodent. 2. Structure elucidation via high resolution, accurate mass LC-MSn revealed that the prominent metabolites of EPZ015666 were present in hepatocytes from all species, with the highest turnover rate in dogs. M1 and M2 resulted from oxidative oxetane ring scission, whereas M3 resulted from loss of the oxetane ring via an N-dealkylation reaction. 3. The formation of M1 and M2 in DLM was significantly abrogated in the presence of the specific CYP2D inhibitor, quinidine, and to a lesser extent by the CYP3A inhibitor, ketoconazole, corroborating data from human recombinant isozymes.
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CAS 1616391-65-1 EPZ015666

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