Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 13, Pages 3052-3059Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.05.014
Keywords
BTK; Covalent kinase inhibitor; Pyrimidine; Structure-activity relationship; Molecular dynamics simulation
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Funding
- National Natural Science Foundation of China [21472244]
- Natural Science Foundation of Jiangsu Province [BK2011626]
- Six Major Talent Peak Project of Jiangsu Province [2011-YY-004]
- Fundamental Research Funds for the Central Universities [2015021]
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A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I-1 exhibited the most potent inhibitory activity with an IC50 value of 0.07 mu M. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization. (C) 2016 Elsevier Ltd. All rights reserved.
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