2. Academic Validation
  3. Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

  • ChemMedChem. 2017 Feb 3;12(3):207-213. doi: 10.1002/cmdc.201600589.
Andrew L McIver  # 1,  Weihe Zhang  # 1,  Qingyang Liu 1,  Xinpeng Jiang 1,  Michael A Stashko 1,  James Nichols 2,  Michael J Miley 3,  Jacqueline Norris-Drouin 1,  Mischa Machius 3,  Deborah DeRyckere 4,  Edgar Wood 2,  Douglas K Graham 4 2,  H Shelton Earp 5 3 2,  Dmitri Kireev 1,  Stephen V Frye 1 5 2,  Xiaodong Wang 1
Affiliations

Affiliations

  • 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.
  • 2 Meryx, Inc., USA.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
  • 5 Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • # Contributed equally.
PMID: 28032464 DOI: 10.1002/cmdc.201600589
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.

Keywords

MerTK; intramolecular hydrogen bonds; kinase inhibitors; macrocycles; pyrimidines.

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