Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

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 Harding, Carlo C. Seña, Tsukasa Sugo, Kozo Hayashi, David McLeod, Carlos Zepeda, Ahmed Aman, Maria Sánchez-Osuna, Eric Bonneil, Shinji Takagi, Rima Al-Awar, Mike Tyers, Stephane Richard, Masayuki Takizawa, Anne-Claude Gingras, Cheryl H. Arrowsmith, Masoud Vedadi, Peter J. Brown, Hiroshi Nara () and Dalia Barsyte-Lovejoy ()
Additional contact information
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
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
Masoud Vedadi: University of Toronto
Peter J. Brown: University of Toronto
Hiroshi Nara: Research, Takeda Pharmaceutical Company Limited
Dalia Barsyte-Lovejoy: University of Toronto

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16271-z

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