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ChemMedChem. 2017 Jan 5;12(1):86-99. doi: 10.1002/cmdc.201600387. Epub 2016 Dec 5.

Design, Synthesis, and Evaluation of Dasatinib-Amino Acid and Dasatinib-Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors.

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Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA, 92618, USA.
Department of Cell & Molecular Biology, University of Rhode Island, 389 CBLS Building, 120 Flagg Road, Kingston, RI, 02881, USA.
Schmid College of Science and Technology Physics, Computational Science and Engineering, Chapman University, Orange, CA, 92866, USA.


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 IC50 values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C10 ) with an IC50 value of 3.2 μm for Csk compared with 35 nm 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 IC50 ratios). Das-R (IC50 =2.06 μm) was significantly more potent than the parent dasatinib (IC50 =26.3 μm) against Panc-1 cells, whereas both compounds showed IC50 <51.2 pm 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.


amino acids; dasatinib; fatty acids; inhibitors; tyrosine kinase

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