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
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
Meryx, Inc., USA.
ChemMedChem. 2017 Feb 3;12(3):207-213. doi: 10.1002/cmdc.201600589. Epub 2017 Jan 9.
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.
大环化合物最近在药物研发中引起了广泛关注。事实上，一些全新设计的大环激酶抑制剂目前正处于临床试验阶段，对其预期靶点具有良好的活性和选择性。在本研究中，我们成功采用基于结构的药物设计方法，发现了大环嘧啶类化合物作为有效的Mer酪氨酸激酶（MerTK）特异性抑制剂。采用384孔板形式的酶联免疫吸附测定（ELISA），在基于细胞的分析中评估大环化合物对MerTK酪氨酸磷酸化的抑制活性。通过构效关系（SAR）研究，类似物11 [UNC2541；（S）-7-氨基-N-（4-氟苄基）-8-氧代-2,9,16-三氮杂-1（2,4）-嘧啶并环十六碳酰胺]被鉴定为一种有效的MerTK特异性抑制剂，在基于细胞的ELISA中表现出亚微摩尔级的抑制活性。此外，解析了MerTK蛋白与11复合物的X射线结构，表明这些大环化合物结合在MerTK的ATP口袋中。
