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

  • ACS Med Chem Lett. 2015 Mar 4;6(5):491-5. doi: 10.1021/acsmedchemlett.5b00037.
John E Campbell  1 ,  Kevin W Kuntz  1 ,  Sarah K Knutson  1 ,  Natalie M Warholic  1 ,  Heike Keilhack  1 ,  Tim J Wigle  1 ,  Alejandra Raimondi  1 ,  Christine R Klaus  1 ,  Nathalie Rioux  1 ,  Akira Yokoi  2 ,  Satoshi Kawano  2 ,  Yukinori Minoshima  2 ,  Hyeong-Wook Choi  3 ,  Margaret Porter Scott  1 ,  Nigel J Waters  1 ,  Jesse J Smith  1 ,  Richard Chesworth  1 ,  Mikel P Moyer  1 ,  Robert A Copeland  1
Affiliations
  • 1. Epizyme, Inc. , 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States.
  • 2. Eisai Co., Ltd. , Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan.
  • 3. Eisai, Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.
PMID: 26005520 DOI: 10.1021/acsmedchemlett.5b00037
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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