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TitleDiscovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.
Journal, issue, pagesJ Med Chem, Vol. 64, Issue 15, Page 11148-11168, Year 2021
Publish dateAug 12, 2021
AuthorsDavid C McKinney / Brian J McMillan / Matthew J Ranaghan / Jamie A Moroco / Merissa Brousseau / Zachary Mullin-Bernstein / Meghan O'Keefe / 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 /
PubMed AbstractPRMT5 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 ...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.
External linksJ Med Chem / PubMed:34342224 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.88 - 2.39 Å
Structure data

23609

7m05

EMDB-23609: PRMT5 bound to covalent PBM-site inhibitor BRD-6988
PDB-7m05: CryoEM structure of PRMT5 bound to covalent PBM-site inhibitor BRD-6988
Method: EM (single particle) / Resolution: 2.39 Å

PDB-6v0p:
PRMT5 complex bound to covalent PBM inhibitor BRD6711
Method: X-RAY DIFFRACTION / Resolution: 1.88 Å

Chemicals

ChemComp-QN4:
2-(5-chloro-6-oxopyridazin-1(6H)-yl)-N-(4-methyl-3-sulfamoylphenyl)acetamide

ChemComp-CL:
Unknown entry / Chloride

ChemComp-SFG:
SINEFUNGIN

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-HOH:
WATER / Water

ChemComp-YJG:
2-(5-chloro-6-oxopyridazin-1(6H)-yl)-N-(4-methyl-3-{[2-(pyridin-2-yl)ethyl]sulfamoyl}phenyl)acetamide

Source
  • homo sapiens (human)
KeywordsSPLICING/TRANSFERASE / methyltransferase / splicing / SDMA / epigenetic / SPLICING-TRANSFERASE complex / TRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR complex

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