Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics*.
Alanine
/ chemistry
Antineoplastic Agents
/ chemical synthesis
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors
/ chemical synthesis
HEK293 Cells
Humans
Indoles
/ chemical synthesis
Molecular Structure
Neoplasms
/ drug therapy
Protein-Arginine N-Methyltransferases
/ antagonists & inhibitors
Structure-Activity Relationship
co-crystal structures
methylation
protein arginine methyl transferases
structure-based drug design
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
08 04 2021
08 04 2021
Historique:
received:
08
01
2021
pubmed:
30
1
2021
medline:
29
12
2021
entrez:
29
1
2021
Statut:
ppublish
Résumé
Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure-based design of a new class of alanine-containing 3-arylindoles as potent and selective PRMT4 inhibitors, and describe key structure-activity relationships for this class of compounds.
Identifiants
pubmed: 33513288
doi: 10.1002/cmdc.202100018
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Indoles
0
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
coactivator-associated arginine methyltransferase 1
EC 2.1.1.319
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1116-1125Subventions
Organisme : Natural Sciences and Engineering Research Council
ID : 2019-06368
Organisme : NSERC CREATE
ID : 432008-2013
Organisme : NSERC CREATE
ID : 1097737
Organisme : Bayer Pharma AG
Organisme : Boehringer Ingelheim
Organisme : Canada Foundation for Innovation
Organisme : Eshelman Institute for Innovation
Organisme : Genome Canada
Organisme : Ontario Genomics Institute
ID : OGI-055
Organisme : Innovative Medicines Initiative
ID : 115766
Organisme : Janssen, Merck KGaA, Darmstadt, Germany
Organisme : Novartis Pharma AG
Organisme : Ontario Ministry of Research
Organisme : Innovation and Science
Organisme : Wellcome
ID : 106169/ZZ14/Z
Informations de copyright
© 2021 Wiley-VCH GmbH.
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