Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

作者：McIver, Andrew L.; Zhang, Weihe; Liu, Qingyang; Jiang, Xinpeng; Stashko, Michael A.; Nichols, James; Miley, Michael J.; Norris-Drouin, Jacqueline; Machius, Mischa; DeRyckere, Deborah; Wood, Edgar; Graham, Douglas K.; Earp, H. Shelton; Kireev, Dmitri; Frye, Stephen V.; Wang, Xiaodong^*

来源：ChemMedChem, 2017, 12(3): 207-213.

DOI：10.1002/cmdc.201600589

• intramolecular hydrogen bonds
• macrocycles
• MerTK
• kinase inhibitors
• pyrimidines

Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immuno-sorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane- 1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.

• 出版日期2017-2-3
• 单位浙江工业大学