Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor
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- 作者：Renato Ferreira de Freitas ; Mohammad S. Eram ; Magdalena M. Szewczyk ; Holger Steuber ; David Smil ; Hong Wu ; Fengling Li ; Guillermo Senisterra ; Aiping Dong ; Peter J. Brown ; Marion Hitchcock ; Dieter Moosmayer ; Christian M. Stegmann ; Ursula Egner ; Cheryl Arrowsmith ; Dalia Barsyte-Lovejoy ; Masoud Vedadi ; Matthieu Schapira
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：February 11, 2016
- 年：2016
- 卷：59
- 期：3
- 页码：1176-1183
- 全文大小：458K
- ISSN：1520-4804
文摘
Protein methyltransferases (PMTs) are a promising target class in oncology and other disease areas. They are composed of SET domain methyltransferases and structurally unrelated Rossman-fold enzymes that include protein arginine methyltransferases (PRMTs). In the absence of a well-defined medicinal chemistry tool-kit focused on PMTs, most current inhibitors were identified by screening large and diverse libraries of leadlike molecules. So far, no successful fragment-based approach was reported against this target class. Here, by deconstructing potent PRMT inhibitors, we find that chemical moieties occupying the substrate arginine-binding site can act as efficient fragment inhibitors. Screening a fragment library against PRMT6 produced numerous hits, including a 300 nM inhibitor (ligand efficiency of 0.56) that decreased global histone 3 arginine 2 methylation in cells, and can serve as a warhead for the development of PRMT chemical probes.