EPZ015666

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

EPZ015666 (GSK3235025) 是一种有效、选择性、口服的 PRMT5 抑制剂，Ki/IC50 为 5/22 nM。

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.

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.

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.

EPZ-015666 | GSK3235025

Chromatin/Epigenetic

HMTase

PRMT5

Cancer

——

1616391-65-1

383.4442

C20H25N5O3

>98% (HPLC)

DMSO

O=C(C1=NC=NC(NC2COC2)=C1)NC[C@H](O)CN3CC4=C(C=CC=C4)CC3

4-Pyrimidinecarboxamide, N-[(2S)-3-(3,4-dihydro-2(1H)-isoquinolinyl)-2-hydroxypropyl]-6-(3-oxetanylamino)-

(-20℃)

With Ice Pack

≥ 2 years