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

Authors

Rakesh K. Tiwari, Chapman University
Alex Brown, University of Rhode Island
Neda Sadeghiani, Chapman University
Amir Nasrolahi Shirazi, Chapman University
Jared Bolton, University of Rhode Island
Amanda Tse, Chapman University
Gennady Verkhivker, Chapman University
Keykavous Parang, Chapman University
Gongqin Sun, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

1-5-2017

Department

Cell & Molecular Biology

Abstract

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 IC50values 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 IC50value 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 IC50ratios). 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.

Publication Title, e.g., Journal

ChemMedChem

Volume

12

Issue

1

Citation/Publisher Attribution

Tiwari, R. K., Brown, A., Sadeghiani, N., Nasrolahi Shirazi, A., Bolton, J., Tse, A.,...Sun, G. (2017). Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors. ChemMedChem, 12, 86. https://doi.org/10.1002/cmdc.201600387 Available at: https://doi.org/10.1002/cmdc.201600387