title: Discovery of a Dual PRMT5-PRMT7 Inhibitor.
abstract: The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate and symmetrically dimethylate arginine side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control of gene transcription, splicing, and the RAS to ERK transduction cascade. It is believed that PRMT5 and PRMT7 act in conjunction to methylate their substrates, and genetic deletions support the notion that these enzymes derepress cell proliferation and migration in cancer. Using available structures of PRMT5, we designed DS-437, a PRMT5 inhibitor with an IC50 value of 6 μM against both PRMT5 and PRMT7 that is inactive against 29 other human protein-, DNA-, and RNA-methyltransferases and inhibits symmetrical dimethylation of PRMT5 substrates in cells. This compound behaves as a cofactor competitor and represents a valid scaffold to interrogate the potential of the PRMT5-PRMT7 axis as a target for therapy.
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Eram
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Szewczyk
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada ; Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 2M9, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada ; The Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada ; The Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
keywords: PRMT5; PRMT7; inhibitor; methyltransferases