Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors

• Published in: ChemMedChem 2015-12, Vol.10 (12), p.2027-2041
• Main Authors: Francini, Cinzia Maria, Fallacara, Anna Lucia, Artusi, Roberto, Mennuni, Laura, Calgani, Alessia, Angelucci, Adriano, Schenone, Silvia, Botta, Maurizio
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; aminoimidazoles; aminothiazoles; antitumor agents; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Humans; Hydrogen Bonding; Imidazoles - chemical synthesis; Imidazoles - chemistry; inhibitors; Inhibitory Concentration 50; Molecular Docking Simulation; Molecular Sequence Data; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Structure, Tertiary; Sequence Alignment; Src kinase; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Structure-Activity Relationship; Thermodynamics; Thiazoles - chemical synthesis; Thiazoles - chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500428

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. Family business: Herein we report the synthesis, biological evaluation, and molecular modeling studies of new 4‐aminoimidazole and 2‐aminothiazole derivatives as Src family kinase (SFK) inhibitors. A few of these candidates were found to be more active against c‐Src than toward other SFKs. We investigated the feasibility of effectively replacing the 2‐aminothiazole moiety with a 4‐aminoimidazole scaffold.