by
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;
Deborah DeRyckere;
Dr. Edgar Wood;
Doug Graham;
Prof. H Shelton Earp;
Prof. Dmitri Kireev;
Prof. Stephen V. Frye;
Prof. Xiaodong Wang
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.