Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors
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- 作者：Dr. Andrew L. McIver ; Dr. Weihe Zhang ; Dr. Qingyang Liu ; Dr. Xinpeng Jiang ; Michael A. Stashko ; James Nichols ; Dr. Michael J. Miley ; Dr. Jacqueline Norris-Drouin ; Dr. Mischa Machius ; Prof. Deborah DeRyckere ; Dr. Edgar Wood ; Prof. Douglas K. Graham ; Prof. H. Shelton Earp ; Prof. Dmitri Kireev ; Prof. Stephen V. Frye and Prof. Xiaodong Wang
- 刊名：ChemMedChem
- 出版年：2017
- 出版时间：February 3, 2017
- 年：2017
- 卷：12
- 期：3
- 页码：207-213
- 全文大小：1418K
- ISSN：1860-7187
文摘
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 immunosorbent 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.