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
  • 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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