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Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors
Author(s) -
Tiwari Rakesh K.,
Brown Alex,
Sadeghiani Neda,
Shirazi Amir Nasrolahi,
Bolton Jared,
Tse Amanda,
Verkhivker Gennady,
Parang Keykavous,
Sun Gongqin
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600387
Subject(s) - dasatinib , proto oncogene tyrosine protein kinase src , chemistry , tyrosine kinase , abl , selectivity , tyrosine protein kinase csk , kinase , tyrosine , biochemistry , stereochemistry , sh3 domain , signal transduction , catalysis
Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib– l ‐arginine derivative (Das‐R, 7 ) was found to be the most potent of the inhibitors tested, with IC 50 values of 4.4, <0.25, and <0.45 n m against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das‐C 10 ) with an IC 50 value of 3.2 μ m for Csk compared with 35 n m for Src. Furthermore, many compounds displayed increased selectivity toward Src over Abl. Compounds 15 (Das–glutamic acid) and 13 (Das–cysteine) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC 50 ratios). Das‐R (IC 50 =2.06 μ m ) was significantly more potent than the parent dasatinib (IC 50 =26.3 μ m ) against Panc‐1 cells, whereas both compounds showed IC 50 <51.2 p m against BV‐173 and K562 cells. Molecular modeling and binding free energy simulations revealed good agreements with the experimental results and rationalized the differences in selectivity among the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of the dasatinib scaffold, providing useful insight into mechanisms of kinase selectivity.