dasatinib and Neuroblastoma

c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.

Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Circular Dichroism; Crystallography, X-Ray; CSK Tyrosine-Protein Kinase; Drug Design; Drug Discovery; Humans; Male; Mice, Nude; Models, Chemical; Models, Molecular; Molecular Structure; Monte Carlo Method; Neuroblastoma; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrazoles; Pyrimidines; src-Family Kinases; Thermodynamics; Xenograft Model Antitumor Assays