title: Design, Synthesis, and Evaluation of Dasatinib-Amino Acid and Dasatinib-Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors.
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.
authors.affiliation: Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA, 92618, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Tiwari
authors.affiliation: Department of Cell & Molecular Biology, University of Rhode Island, 389 CBLS Building, 120 Flagg Road, Kingston, RI, 02881, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Brown
authors.affiliation: Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA, 92618, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Sadeghiani
authors.affiliation: Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA, 92618, USA.
authors.forename: Amir Nasrolahi
authors.initials: AN
authors.lastname: Shirazi
authors.affiliation: Department of Cell & Molecular Biology, University of Rhode Island, 389 CBLS Building, 120 Flagg Road, Kingston, RI, 02881, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Bolton
authors.affiliation: Schmid College of Science and Technology Physics, Computational Science and Engineering, Chapman University, Orange, CA, 92866, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Tse
authors.affiliation: Schmid College of Science and Technology Physics, Computational Science and Engineering, Chapman University, Orange, CA, 92866, USA.
authors.forename: Gennady
authors.initials: G
authors.lastname: Verkhivker
authors.affiliation: Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA, 92618, USA.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.affiliation: Department of Cell & Molecular Biology, University of Rhode Island, 389 CBLS Building, 120 Flagg Road, Kingston, RI, 02881, USA.
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib
keywords: amino acids; dasatinib; fatty acids; inhibitors; tyrosine kinase