title: Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors.
abstract: Src family kinases (SFKs) are a family of non-receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c-Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4-aminoimidazole and 2-aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2-aminothiazole analogues of dasatinib and 4-aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with Ki values in the range of 90-480 nm. A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH-SY5Y and K562 cell lines. Compound 3 b [2-(4-{2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)ethanol] was found to be the most active inhibitor.
authors.affiliation: Medicinal Chemistry Division, Rottapharm Biotech S.r.l., Valosa di Sopra N 9 Street, 20900, Monza, Italy.
authors.forename: Cinzia Maria
authors.initials: CM
authors.lastname: Francini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fallacara
authors.affiliation: Medicinal Chemistry Division, Rottapharm Biotech S.r.l., Valosa di Sopra N 9 Street, 20900, Monza, Italy. roberto.artusi@rottapharmbiotech.com.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artusi
authors.affiliation: Pharmacology and Toxicology Division, Rottapharm Biotech S.r.l., Valosa di Sopra N 9 Street, 20900, Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologie, Università dell'Aquila, Via Vetoio Coppito, 67100, L'Aquila, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Calgani
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologie, Università dell'Aquila, Via Vetoio Coppito, 67100, L'Aquila, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132, Genova, Italy. schensil@unige.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA, 19122, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D019061:src-Family Kinases
keywords: Src kinase; aminoimidazoles; aminothiazoles; antitumor agents; inhibitors