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

Adaptor Proteins, Signal Transducing / antagonists & inhibitors Dose-Response Relationship, Drug Drug Discovery Humans Models, Molecular Molecular Structure Protein-Arginine N-Methyltransferases / antagonists & inhibitors Pyridazines / chemical synthesis Structure-Activity Relationship

Journal

Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531

Informations de publication

Date de publication:
12 08 2021
Historique:
pubmed: 4 8 2021
medline: 9 3 2022
entrez: 3 8 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1021/acs.jmedchem.1c00507 PMID: 34342224 PMC: PMC9036822
pubmed: 34342224
doi: 10.1021/acs.jmedchem.1c00507
pmc: PMC9036822
mid: NIHMS1786730
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
Pyridazines 0
PRMT5 protein, human EC 2.1.1.319
Protein-Arginine N-Methyltransferases EC 2.1.1.319

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

11148-11168

Subventions

Organisme : NCI NIH HHS
ID : R01 CA233626
Pays : United States

Références

Cancer Cell. 2021 Feb 8;39(2):209-224.e11
pubmed: 33450196
Elife. 2018 Mar 07;7:
pubmed: 29513216
Science. 2016 Mar 11;351(6278):1214-8
pubmed: 26912360
PLoS One. 2018 Mar 8;13(3):e0193205
pubmed: 29518110
Science. 2016 Mar 11;351(6278):1208-13
pubmed: 26912361
ACS Med Chem Lett. 2018 Apr 23;9(7):612-617
pubmed: 30034588
Cell. 2017 Jul 27;170(3):577-592.e10
pubmed: 28753431
J Med Chem. 2020 Sep 10;63(17):9977-9989
pubmed: 32787082
Nat Rev Drug Discov. 2020 Jan;19(1):23-38
pubmed: 31712683
J Org Chem. 2013 Jun 7;78(11):5160-71
pubmed: 23692141
Mod Pathol. 2010 Apr;23(4):531-8
pubmed: 20081810
Drug Metab Pharmacokinet. 2012;27(5):466-77
pubmed: 22813719
Biomed Pharmacother. 2019 Jun;114:108790
pubmed: 30903920
Biochem Pharmacol. 2005 Nov 25;70(11):1673-84
pubmed: 16213467
Mol Cell. 2021 Sep 2;81(17):3481-3495.e7
pubmed: 34358446
Drug Metab Dispos. 2015 Mar;43(3):375-84
pubmed: 25504185
SLAS Discov. 2017 Jan;22(1):3-20
pubmed: 27703080
Nat Chem Biol. 2015 Jun;11(6):432-7
pubmed: 25915199
J Med Chem. 2013 Sep 12;56(17):7025-48
pubmed: 23930994
Sci Signal. 2019 Apr 02;12(575):
pubmed: 30940768

Auteurs

David C McKinney (DC)

Center 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 McMillan (BJ)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Matthew J Ranaghan (MJ)

Center 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 Moroco (JA)

Center 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 Brousseau (M)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Zachary Mullin-Bernstein (Z)

Cancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Meghan O'Keefe (M)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Patrick McCarren (P)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Michael F Mesleh (MF)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Kathleen M Mulvaney (KM)

Cancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Foxy Robinson (F)

Cancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Ritu Singh (R)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Besnik Bajrami (B)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Florence F Wagner (FF)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Robert Hilgraf (R)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Martin J Drysdale (MJ)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Arthur J Campbell (AJ)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Adam Skepner (A)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

David E Timm (DE)

Department of Biochemistry, University of Utah, 1390 Presidents Circle, Salt Lake City, Utah 84112, United States.

Dale Porter (D)

Cancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

Virendar K Kaushik (VK)

Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.

William R Sellers (WR)

Cancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02215, United States.

Alessandra Ianari (A)

Cancer Program, The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
ORCID: 0000-0002-5850-0476

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Protein-arginine N-methyltransferases › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridazines › Discovery of a First-in-Class Inhibitor of the...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Discovery of a First-in-Class Inhibitor of the...