Abstract

Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

  • Compound C24H32N2O2

    EPZ007345

  • Compound C20H25N5O3

    EPZ015666

  • Compound C16H25N5O3

    EPZ019896

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Acknowledgements

We acknowledge team members from Epizyme, Inc. (E.C.-P., K.G.K., C.R.M., P.A.B.-S., T.J.W., L.D.J., N.R., M.J.M., L.J., S.L.J., K.A.W., T.L., K.S., S.A.R., A.R., M.P.S., N.J.W., R.M.P., J.J.S., M.P.M., R.A.C., R.C. and K.W.D.) and GlaxoSmithKline (O.B., M.P., T.F.H., K.N., K.P.O., K.T.G. and R.K.) for their contributions to this manuscript.

Author information

Author notes

    • Elayne Chan-Penebre
    • , Kristy G Kuplast
    •  & Kenneth W Duncan

    These authors contributed equally to this work.

Affiliations

  1. Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.

    • Elayne Chan-Penebre
    • , Kristy G Kuplast
    • , P Ann Boriack-Sjodin
    • , L Danielle Johnston
    • , Nathalie Rioux
    • , Michael J Munchhof
    • , Suzanne L Jacques
    • , Kip A West
    • , Trupti Lingaraj
    • , Kimberly Stickland
    • , Scott A Ribich
    • , Alejandra Raimondi
    • , Nigel J Waters
    • , Jesse J Smith
    • , Robert A Copeland
    • , Richard Chesworth
    •  & Kenneth W Duncan
  2. Warp Drive Bio, Cambridge, Massachusetts, USA.

    • Christina R Majer
    • , Tim J Wigle
    •  & Roy M Pollock
  3. Agile Biostructure Solutions, Cambridge, Massachusetts, USA.

    • Lei Jin
  4. Genentech, San Francisco, California, USA.

    • Margaret Porter Scott
  5. Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

    • Olena Barbash
    • , Melissa Pappalardi
    •  & Ryan Kruger
  6. Department of Biological Reagents and Assay Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

    • Thau F Ho
    • , Kelvin Nurse
    •  & Khyati P Oza
  7. Discovery Core Technologies and Capabilities, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

    • Kathleen T Gallagher
  8. Raze Therapeutics, Cambridge, Massachusetts, USA.

    • Mikel P Moyer

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Contributions

K.W.D., M.J.M. and R.C. designed compounds. L.J. and P.A.B.-S. performed X-ray crystallography and produced X-ray protein. M.P., T.F.H., K.N., K.P.O. and K.T.G. made the initial protein for biochemistry. E.C.-P., K.G.K., T.L. and L.D.J. performed in vitro methyl mark and proliferation studies. N.R. and N.J.W. performed ADME pharmacokinetics studies. E.C.-P., K.G.K., R.M.P. and K.A.W. ran in vivo studies. C.R.M. and T.J.W. ran biochemical and SPR studies. K.W.D., E.C.-P., K.G.K., S.L.J., M.P.S., M.P.M., R.A.C., O.B., R.K., N.J.W., N.R., K.S., J.J.S., R.C., A.R. and S.A.R. designed studies and interpreted results. K.W.D., E.C.-P., K.G.K., T.J.W. and P.A.B.-S. wrote the paper.

Competing interests

E.C.-P., K.G.K., C.R.M., P.A.B.-S., T.J.W., L.D.J., N.R., L.J., S.L.J., K.A.W., T.L., K.S., S.A.R., A.R., M.P.S., N.J.W., R.M.P., J.J.S., M.P.M., R.A.C., R.C. and K.W.D. were employees of Epizyme, Inc. at the time of the studies. O.B., M.P., T.F.H., K.N., K.P.O., K.T.G. and R.K. were employees of GSK at the time of the studies. M.J.M. is a consultant for Epizyme, Inc.

Corresponding author

Correspondence to Kenneth W Duncan.

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https://doi.org/10.1038/nchembio.1810

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