1. A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6
- Author
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Jian Jin, Levon Halabelian, Fengling Li, Masoud Vedadi, Rima Al-awar, Carlo C. dela Seña, Mohammad S. Eram, Aiping Dong, Carlos Zepeda-Velázquez, He Chen, Matthieu Schapira, Robert M. Campbell, Dalia Barsyte-Lovejoy, David McLeod, Cheryl H. Arrowsmith, Hong Zeng, Hong Wu, Yudao Shen, Mary M. Mader, Viacheslav V. Trush, Brian Morgan Watson, Kwang-Su Park, Irene Chau, Fanye Meng, Peter Brown, H. Ümit Kaniskan, and Magdalena M. Szewczyk
- Subjects
Protein-Arginine N-Methyltransferases ,Methyltransferase ,Arginine ,Stereochemistry ,Cell ,Allosteric regulation ,Crystallography, X-Ray ,01 natural sciences ,Article ,03 medical and health sciences ,Allosteric Regulation ,Drug Discovery ,medicine ,Humans ,Enzyme Inhibitors ,IC50 ,030304 developmental biology ,Benzodiazepinones ,0303 health sciences ,Chemistry ,Nuclear Proteins ,Stereoisomerism ,Highly selective ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,medicine.anatomical_structure ,Molecular Medicine ,Enantiomer ,Selectivity ,Allosteric Site ,Protein Binding - Abstract
Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (R)-2 (SGC6870). (R)-2 is a potent PRMT6 inhibitor (IC(50) = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6−(R)-2 complex and kinetic studies revealed (R)-2 binds a unique, induced allosteric pocket. Additionally, (R)-2 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, (R)-2’s enantiomer, (S)-2 (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, (R)-2 is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.
- Published
- 2021