Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Aug 3

PMID 34342224

Citations 18

Authors

David C McKinney

Brian J McMillan

Matthew J Ranaghan

Jamie A Moroco

Merissa Brousseau

Zachary Mullin-Bernstein

Meghan OKeefe

Patrick McCarren

Michael F Mesleh

Kathleen M Mulvaney

Foxy Robinson

Ritu Singh

Besnik Bajrami

Florence F Wagner

Robert Hilgraf

Martin J Drysdale

Arthur J Campbell

Adam Skepner

David E Timm

Dale Porter

Virendar K Kaushik

William R Sellers

Alessandra Ianari

Affiliations

Soon will be listed here.

Abstract

PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed the formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.

Citing Articles

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Substrate adaptors are flexible tethering modules that enhance substrate methylation by the arginine methyltransferase PRMT5.

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Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB.

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