A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models


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.

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Figure 1: Identification, characterization and optimization of diversity high-throughput screening (HTS) hit to a potent and selective inhibitor of PRMT5.
Figure 2: Characterization of EPZ015666 binding mode using X-ray crystallography and surface plasmon resonance.
Figure 3: Effects of EPZ015666 and control compound 3 on cellular target inhibition as determined by SMDA western blot and CETSA.
Figure 4: EPZ015666 effects on in vitro cellular proliferation and in vivo antitumor activity in MCL cell lines and xenografts in SCID mice.

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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.

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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.

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Correspondence to Kenneth W Duncan.

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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.

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Chan-Penebre, E., Kuplast, K., Majer, C. et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol 11, 432–437 (2015). https://doi.org/10.1038/nchembio.1810

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