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.
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Elayne
E
Chan-Penebre
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Kristy G
KG
Kuplast
Warp Drive Bio, Cambridge, Massachusetts, USA.
Christina R
CR
Majer
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
P Ann
PA
Boriack-Sjodin
Warp Drive Bio, Cambridge, Massachusetts, USA.
Tim J
TJ
Wigle
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
L Danielle
LD
Johnston
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Nathalie
N
Rioux
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Michael J
MJ
Munchhof
Agile Biostructure Solutions, Cambridge, Massachusetts, USA.
Lei
L
Jin
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Suzanne L
SL
Jacques
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Kip A
KA
West
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Trupti
T
Lingaraj
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Kimberly
K
Stickland
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Scott A
SA
Ribich
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Alejandra
A
Raimondi
Genentech, San Francisco, California, USA.
Margaret Porter
MP
Scott
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Nigel J
NJ
Waters
Warp Drive Bio, Cambridge, Massachusetts, USA.
Roy M
RM
Pollock
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Jesse J
JJ
Smith
Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Olena
O
Barbash
Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Melissa
M
Pappalardi
Department of Biological Reagents and Assay Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Thau F
TF
Ho
Department of Biological Reagents and Assay Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Kelvin
K
Nurse
Department of Biological Reagents and Assay Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Khyati P
KP
Oza
Discovery Core Technologies and Capabilities, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Kathleen T
KT
Gallagher
Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Ryan
R
Kruger
Raze Therapeutics, Cambridge, Massachusetts, USA.
Mikel P
MP
Moyer
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Robert A
RA
Copeland
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Richard
R
Chesworth
Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.
Kenneth W
KW
Duncan
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008745:Methylation; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D055517:snRNP Core Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; C000599896:GSK3235025; D007546:Isoquinolines; D011743:Pyrimidines; C526412:SNRPD3 protein, human; D055517:snRNP Core Proteins; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases