1. Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics*.
- Author
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Sutherland M, Li A, Kaghad A, Panagopoulos D, Li F, Szewczyk M, Smil D, Scholten C, Bouché L, Stellfeld T, Arrowsmith CH, Barsyte D, Vedadi M, Hartung IV, Steuber H, Britton R, and Santhakumar V
- Subjects
- Alanine chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, HEK293 Cells, Humans, Indoles chemical synthesis, Indoles chemistry, Molecular Structure, Neoplasms metabolism, Protein-Arginine N-Methyltransferases genetics, Protein-Arginine N-Methyltransferases metabolism, Structure-Activity Relationship, Alanine pharmacology, Antineoplastic Agents pharmacology, Drug Design, Enzyme Inhibitors pharmacology, Indoles pharmacology, Neoplasms drug therapy, Protein-Arginine N-Methyltransferases antagonists & inhibitors
- Abstract
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., (© 2021 Wiley-VCH GmbH.)
- Published
- 2021
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