Author
Listed:
- Magdalena M. Szewczyk
(University of Toronto)
- Yoshinori Ishikawa
(Research, Takeda Pharmaceutical Company Limited)
- Shawna Organ
(University of Toronto)
- Nozomu Sakai
(Research, Takeda Pharmaceutical Company Limited)
- Fengling Li
(University of Toronto)
- Levon Halabelian
(University of Toronto)
- Suzanne Ackloo
(University of Toronto)
- Amber L. Couzens
(Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute)
- Mohammad Eram
(University of Toronto)
- David Dilworth
(University of Toronto)
- Hideto Fukushi
(Research, Takeda Pharmaceutical Company Limited)
- Rachel Harding
(University of Toronto)
- Carlo C. Seña
(University of Toronto)
- Tsukasa Sugo
(Research, Takeda Pharmaceutical Company Limited)
- Kozo Hayashi
(Research, Takeda Pharmaceutical Company Limited)
- David McLeod
(Drug Discovery Program, Ontario Institute for Cancer Research)
- Carlos Zepeda
(Drug Discovery Program, Ontario Institute for Cancer Research)
- Ahmed Aman
(Drug Discovery Program, Ontario Institute for Cancer Research)
- Maria Sánchez-Osuna
(Institute for Research in Immunology and Cancer (IRIC) University of Montreal)
- Eric Bonneil
(Institute for Research in Immunology and Cancer (IRIC) University of Montreal)
- Shinji Takagi
(Research, Takeda Pharmaceutical Company Limited)
- Rima Al-Awar
(Drug Discovery Program, Ontario Institute for Cancer Research
University of Toronto)
- Mike Tyers
(Institute for Research in Immunology and Cancer (IRIC) University of Montreal)
- Stephane Richard
(McGill University)
- Masayuki Takizawa
(Research, Takeda Pharmaceutical Company Limited)
- Anne-Claude Gingras
(Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute)
- Cheryl H. Arrowsmith
(University of Toronto
University of Toronto)
- Masoud Vedadi
(University of Toronto
University of Toronto)
- Peter J. Brown
(University of Toronto)
- Hiroshi Nara
(Research, Takeda Pharmaceutical Company Limited)
- Dalia Barsyte-Lovejoy
(University of Toronto
University of Toronto
Nature Research Center)
Abstract
Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
Suggested Citation
Magdalena M. Szewczyk & Yoshinori Ishikawa & Shawna Organ & Nozomu Sakai & Fengling Li & Levon Halabelian & Suzanne Ackloo & Amber L. Couzens & Mohammad Eram & David Dilworth & Hideto Fukushi & Rachel, 2020.
"Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response,"
Nature Communications, Nature, vol. 11(1), pages 1-15, December.
Handle:
RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16271-z
DOI: 10.1038/s41467-020-16271-z
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