Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

Andrew L. McIver, Weihe Zhang, Qingyang Liu, Xinpeng Jiang, Michael A. Stashko, James Nichols, Michael J. Miley, Jacqueline Norris-Drouin, Mischa Machius, Deborah DeRyckere, Edgar Wood, Douglas K. Graham, H. Shelton Earp, Dmitri Kireev, Stephen V. Frye, Xiaodong Wang

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages207-213
Number of pages7
JournalChemMedChem
Volume12
Issue number3
DOIs
StatePublished - Jan 1 2017

Fingerprint

Pyrimidines
Protein-Tyrosine Kinases
Assays
Immunosorbents
Enzyme-Linked Immunosorbent Assay
Phosphorylation
Drug Design
Enzymes
Drug Discovery
Structure-Activity Relationship
Tyrosine
Phosphotransferases
Adenosine Triphosphate
X-Rays
Clinical Trials
X rays
Pharmaceutical Preparations

Keywords

  • intramolecular hydrogen bonds
  • kinase inhibitors
  • macrocycles
  • MerTK
  • pyrimidines

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

McIver, A. L., Zhang, W., Liu, Q., Jiang, X., Stashko, M. A., Nichols, J., ... Wang, X. (2017). Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors. ChemMedChem, 12(3), 207-213. DOI: 10.1002/cmdc.201600589

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors. / McIver, Andrew L.; Zhang, Weihe; Liu, Qingyang; Jiang, Xinpeng; Stashko, Michael A.; Nichols, James; Miley, Michael J.; Norris-Drouin, Jacqueline; Machius, Mischa; DeRyckere, Deborah; Wood, Edgar; Graham, Douglas K.; Earp, H. Shelton; Kireev, Dmitri; Frye, Stephen V.; Wang, Xiaodong.

In: ChemMedChem, Vol. 12, No. 3, 01.01.2017, p. 207-213.

Research output: Contribution to journalArticle

McIver, AL, Zhang, W, Liu, Q, Jiang, X, Stashko, MA, Nichols, J, Miley, MJ, Norris-Drouin, J, Machius, M, DeRyckere, D, Wood, E, Graham, DK, Earp, HS, Kireev, D, Frye, SV & Wang, X 2017, 'Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors' ChemMedChem, vol. 12, no. 3, pp. 207-213. DOI: 10.1002/cmdc.201600589
McIver AL, Zhang W, Liu Q, Jiang X, Stashko MA, Nichols J et al. Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors. ChemMedChem. 2017 Jan 1;12(3):207-213. Available from, DOI: 10.1002/cmdc.201600589
McIver, Andrew L. ; Zhang, Weihe ; Liu, Qingyang ; Jiang, Xinpeng ; Stashko, Michael A. ; Nichols, James ; Miley, Michael J. ; Norris-Drouin, Jacqueline ; Machius, Mischa ; DeRyckere, Deborah ; Wood, Edgar ; Graham, Douglas K. ; Earp, H. Shelton ; Kireev, Dmitri ; Frye, Stephen V. ; Wang, Xiaodong. / Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors. In: ChemMedChem. 2017 ; Vol. 12, No. 3. pp. 207-213
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