Evidence map›Paper›PMID 34342224›Full record

ArticleJournal of medicinal chemistry2021

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

David 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 and 13 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
3.3field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 52 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Review
  5. Article
  6. Article
  7. Exploiting Synthetic Lethality of PRMT5 for Precision Treatment of MTAP-Deficient Glioblastoma.International journal of translational medicine (Basel, Switzerland) · 2025
    Article
  8. Review
  9. Article
  10. Article
  11. Article
  12. Review
  13. Article
  14. Review
  15. Review
  16. Taming PRMT5-adaptor protein interactions.Trends in pharmacological sciences · 2023
    Article
  17. The potential and challenges of targetingFrontiers in oncology · 2023
    Review
  18. Review
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 2 institutions in 1 country.

David C McKinneyCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.ORCID 0000-0003-1787-1841
Brian J McMillanCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Matthew J RanaghanCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.ORCID 0000-0003-3572-5127
Jamie A MorocoCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.ORCID 0000-0001-8250-5923
Merissa BrousseauCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Zachary Mullin-BernsteinCancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Meghan O'KeefeCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Patrick McCarrenCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Michael F MeslehCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Kathleen M MulvaneyCancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Foxy RobinsonCancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Ritu SinghCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Besnik BajramiCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Florence F WagnerCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Robert HilgrafCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Martin J DrysdaleCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Arthur J CampbellCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Adam SkepnerCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
David E TimmDepartment of Biochemistry, University of Utah, 1390 Presidents Circle, Salt Lake City, Utah 84112, United States.
Dale PorterCancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Virendar K KaushikCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
William R SellersCancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Alessandra IanariCancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.ORCID 0000-0002-5850-0476
Broad Institute · USUniversity of Utah · US

Funding

The function of the PRMT5 methylosome in MTAP deleted cancersR01CA233626 · NCI · BROAD INSTITUTE, INC. · PI Andrew James Aguirre, WILLIAM R SELLERS · 2019 to 2026
$2.9M
NCI NIH HHS R01 CA233626
6 · The paper itself

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.

Indexed as

Drug DiscoveryAdaptor Proteins, Signal TransducingDose-Response Relationship, DrugHumansModels, MolecularMolecular StructureProtein-Arginine N-MethyltransferasesPyridazinesStructure-Activity RelationshipAdaptor Proteins, Signal TransducingPRMT5 protein, humanProtein-Arginine N-MethyltransferasesPyridazines

Identifiers

PMID34342224
PMCPMC9036822
OpenAlexW3189196802

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.