title: Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors.
abstract: 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.
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: McIver
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.affiliation: Meryx, Inc., USA.
authors.forename: James
authors.initials: J
authors.lastname: Nichols
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Norris-Drouin
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Mischa
authors.initials: M
authors.lastname: Machius
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.affiliation: Meryx, Inc., USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Wood
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.|Meryx, Inc., USA.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Meryx, Inc., USA.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.|Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Meryx, Inc., USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D047028:Macrocyclic Compounds / Q000737:chemistry; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000076202:c-Mer Tyrosine Kinase
chemical_list: D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: MerTK; intramolecular hydrogen bonds; kinase inhibitors; macrocycles; pyrimidines