EPZ015666

SKU: orb1226052

Description

EPZ015666 (GSK3235025) is a potent, selective, orally available inhibitor of PRMT5 with Ki/IC50 of 5/22 nM, displays broad selectivity against a panel of other histone methyltransferases; inhibits SmD3 methylation and causes cell death in MCL cell lines (IC50=61-904 nM), demonstrates potent concentration-dependent antiproliferative effects against Z-138 and Maver-1 cells with IC50 of 96 and 450 nM, respectively; exhibits antitumor activity in multiple MCL xenograft models.

Key Properties

• CAS Number: 1616391-65-1
• MW: 383.4442
• Purity: >98% (HPLC)
• Formula: C₂₀H₂₅N₅O₃
• SMILES: O=C(C1=NC=NC(NC2COC2)=C1)NC[C@H](O)CN3CC4=C(C=CC=C4)CC3
• Target: HMTase
• Solubility: DMSO

Bioactivity

• In Vivo:
  EPZ015666 (GSK3235025) is orally bioavailable and amenable to In vivo studies. We performed 21-d efficacy studies in severe combined immunodeficiency (SCID) mice bearing subcutaneous Z-138 and Maver-1 xenografts, with twice-daily (BID) oral dosing on four dose groups: 25, 50, 100 and 200 mg per kilogram of body weight (mg/kg). After 21 d of continuous dosing, animals are euthanized, and blood and tissues are analyzed to determine the relationship between methyl-mark pharmacodynamics and tumor-growth inhibition (TGI). EPZ015666 (GSK3235025) showed dose-dependent exposure and TGI after 21 d in both MCL models. Tumors in all EPZ015666 (GSK3235025) dose groups measured on day 21 showed statistically significant differences in weight, volume and tumor growth compared to vehicle-treated tumors. Dosing at 200 mg/kg BID induced tumor stasis in Z-138 cells, with >93% TGI after 21 d, whereas Maver-1 cells showed >70% TGI. Additionally, a third MCL xenograft is tested using the Granta-519 cell line, a fast-growing model that reached endpoint on day 18 and showed dose-dependent efficacy with 45% TGI in the 200 mg/kg group. EPZ015666 (GSK3235025) is well tolerated in all three models, with minimal bodyweight loss in the 200 mg/kg dose group and no other clinical observations.
• In Vitro:
  Treatment of MCL cell lines with EPZ015666 (GSK3235025) leads to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. EPZ015666 (GSK3235025), a potent peptide-competitive and SAM-cooperative inhibitor with >10, 000-fold specificity against PRMT5 relative to other methyltransferases.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

EPZ-015666 | GSK3235025

Quick Database Links

Gene Symbol

HMTase