Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening

详细信息    查看全文

• 作者：Renato Ferreira de Freitas ; Mohammad S. Eram ; David Smil ; Magdalena M. Szewczyk ; Steven Kennedy ; Peter J. Brown ; Vijayaratnam Santhakumar ; Dalia Barsyte-Lovejoy ; Cheryl H. Arrowsmith ; Masoud Vedadi ; Matthieu Schapira
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 28, 2016
• 年：2016
• 卷：59
• 期：14
• 页码：6838-6847
• 全文大小：494K
• 年卷期：0
• ISSN：1520-4804

文摘

Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods. Two structure-based rounds of optimization produced 27 (SGC2085), a CARM1 inhibitor with an IC₅₀ of 50 nM and more than hundred-fold selectivity over other PRMTs. These results indicate that virtual screening strategies can be successfully applied to Rossmann-fold protein methyltransferases.