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

被引：103

作者：

Campbell, John E. ^{[1
]}

Kuntz, Kevin W. ^{[1
]}

Knutson, Sarah K. ^{[1
]}

Warholic, Natalie M. ^{[1
]}

Keilhack, Heike ^{[1
]}

Wigle, Tim J. ^{[1
]}

Raimondi, Alejandra ^{[1
]}

Klaus, Christine R. ^{[1
]}

Rioux, Nathalie ^{[1
]}

Yokoi, Akira ^{[2
]}

Kawano, Satoshi ^{[2
]}

Minoshima, Yukinori ^{[2
]}

Choi, Hyeong-Wook ^{[3
]}

Scott, Margaret Porter ^{[1
]}

Waters, Nigel J. ^{[1
]}

Smith, Jesse J. ^{[1
]}

Chesworth, Richard ^{[1
]}

Moyer, Mikel P. ^{[1
]}

Copeland, Robert A. ^{[1
]}

机构：

[1] Epizyme Inc, Cambridge, MA 02139 USA

[2] Eisai & Co Ltd, Tsukuba, Ibaraki 3002635, Japan

[3] Eisai Inc, Andover, MA 01810 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 05期

关键词：

Methyltransferase; PRC2; EZH2; B cell lymphoma; KARPAS-422; xenograft; in vivo chemical probe; HISTONE METHYLTRANSFERASE; LYMPHOMA; IDENTIFICATION; METHYLATION; COMPLEX;

D O I：

10.1021/acsmedchemlett.5b00037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：491 / 495

页数：5

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