Sutherland Mathew, Li Alice, Kaghad Anissa, Panagopoulos Dimitrios, Li Fengling, Szewczyk Magdalena, Smil David, Scholten Cora, Bouché Léa, Stellfeld Timo, Arrowsmith Cheryl H, Barsyte Dalia, Vedadi Masoud, Hartung Ingo V, Steuber Holger, Britton Robert, Santhakumar Vijayaratnam
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.
Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada.
ChemMedChem. 2021 Apr 8;16(7):1116-1125. doi: 10.1002/cmdc.202100018. Epub 2021 Mar 4.
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.
蛋白质精氨酸N-甲基转移酶4（PRMT4）可使组蛋白H3和非组蛋白的精氨酸残基发生不对称二甲基化。PRMT4在多种癌症中的过表达激发了人们对发现抑制剂作为生物学工具以及潜在治疗药物的兴趣。尽管已经报道了几种PRMT4抑制剂，但大多数对PRMT甲基转移酶家族的其他成员选择性较差。在此，我们报告了一类新型含丙氨酸的3-芳基吲哚作为有效且选择性PRMT4抑制剂的基于结构的设计，并描述了这类化合物的关键构效关系。
