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. 2015 Mar 4;6(5):491-5.
doi: 10.1021/acsmedchemlett.5b00037. eCollection 2015 May 14.

EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity

Affiliations

EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity

John E Campbell et al. ACS Med Chem Lett. .

Abstract

Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.

Keywords: B cell lymphoma; EZH2; KARPAS-422; Methyltransferase; PRC2; in vivo chemical probe; xenograft.

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Conflict of interest statement

The authors declare the following competing financial interest(s): J.E.C., K.W.K., S.K.K., N.M.W., H.K., T.J.W., A.R., C.R.K., N.R., M.P.S., N.J.W., J.J.S., R.C., M.P.M., and R.A.C. have ownership interest (including patents) in Epizyme.

Figures

Figure 1
Figure 1
Representative reported EZH2 inhibitors.
Figure 2
Figure 2
SAR affords a potent, stable EZH2 inhibitor.
Figure 3
Figure 3
Effect of EPZ011989 concentration on the proliferation of WSU-DLCL2 cells in culture over an 11-day period.
Figure 4
Figure 4
Single dose PK in SCID mice following oral administration of 125, 250, 500, and 1000 mg/kg dosed as suspensions in 0.5% w/v methyl cellulose and 0.1% Tween-80 acidified with 1 mol equiv of HCl. LCC predicted efficacious plasma level for compound EPZ011989 (158 ng/mL) is shown by a horizontal, dashed line.
Figure 5
Figure 5
(a) Pharmacokinetic analysis of day 7 plasma samples for EPZ011989. (b) Pharmacodynamic analysis of histone methyl mark in bone marrow tissue at day 7 of dosing EPZ011989.
Figure 6
Figure 6
PK after oral dosing of EPZ011989 DTAL at doses of 30, 100, and 300 mg/kg.
Figure 7
Figure 7
Robust tumor growth inhibition seen at 250 and 500 mg/kg BID EPZ011989.
Figure 8
Figure 8
Methyl mark reduction observed in tumor tissue over time on day 7 of EPZ011989 administration.
Figure 9
Figure 9
Total and free plasma exposure time courses for EPZ011989 in the KARPAS-422 xenograft study. Values measured postdose on day 7 of 21.

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