EPZ-015666

• CAT Number: I002063
• CAS Number: 1616391-65-1
• Molecular Formula: C₂₀H₂₅N₅O₃
• Molecular Weight: 383.44
• Purity: ≥95%
• Target: Histone Methyltransferase
• Solubility: DMSO: 60 mg/mL (warmed), H2O: < 1 mg/mL
• Storage: Store at -20°C
• IC50: 5 nM (Ki)
• 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
• InChIKey: ZKXZLIFRWWKZRY-KRWDZBQOSA-N
• SMILES: C1CN(CC2=CC=CC=C21)CC(CNC(=O)C3=CC(=NC=N3)NC4COC4)O

EPZ-015666 (CAT: I002063) is a small-molecule inhibitor that targets the protein arginine methyltransferase 5 (PRMT5). PRMT5 is an enzyme involved in the methylation of histone and non-histone proteins, which plays a crucial role in gene expression regulation. By inhibiting PRMT5, EPZ-015666 disrupts the methylation process and affects downstream cellular processes, including cell proliferation and differentiation. EPZ-015666 has shown promise as a potential therapeutic agent in various cancer types, where PRMT5 is often dysregulated and contributes to tumor growth and progression.

Reference

1. Xenobiotica. 2016;46(3):268-77.

Species differences in metabolism of EPZ015666, an oxetane-containing protein
arginine methyltransferase-5 (PRMT5) inhibitor.

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-MS(n) 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. 4. Our data indicate a marked
species difference in the metabolism of the PRMT5 inhibitor EPZ015666, with
oxetane ring scission the predominant metabolic pathway in dog mediated largely
by CYP2D.

2. ACS Med Chem Lett. 2015 Dec 2;7(2):162-6. doi: 10.1021/acsmedchemlett.5b00380.
eCollection 2016 Feb 11.

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound
EPZ015666.

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).