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Discovery of Macrocyclic Pyrimidines as MerTK‐Specific Inhibitors
Author(s) -
McIver Andrew L.,
Zhang Weihe,
Liu Qingyang,
Jiang Xinpeng,
Stashko Michael A.,
Nichols James,
Miley Michael J.,
NorrisDrouin Jacqueline,
Machius Mischa,
DeRyckere Deborah,
Wood Edgar,
Graham Douglas K.,
Earp H. Shelton,
Kireev Dmitri,
Frye Stephen V.,
Wang Xiaodong
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600589
Subject(s) - mertk , chemistry , tyrosine kinase , drug discovery , structure–activity relationship , phosphorylation , biochemistry , tyrosine , kinase , tyrosine kinase inhibitor , ic50 , stereochemistry , receptor tyrosine kinase , in vitro , biology , signal transduction , genetics , cancer
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.