Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors
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Published on: January 22, 2019
Cinzia Maria Francini1, Anna Lucia Fallacara2, Roberto Artusi3
1Medicinal Chemistry Division, Rottapharm Biotech S.r.l., Valosa di Sopra N 9 Street, 20900, Monza, Italy.
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.
Insights
Researchers developed novel 4-aminoimidazole and 2-aminothiazole compounds as potential inhibitors of Src family kinases (SFKs). The most active compound demonstrated significant antiproliferative effects, offering a promising avenue for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Src family kinases (SFKs) are critical regulators of cellular processes, and their aberrant activity is linked to cancer growth and metastasis.
- c-Src, a specific SFK, is frequently overexpressed or hyperactivated in solid tumors, driving tumor progression and metastasis.
Purpose of the Study:
- To synthesize and evaluate novel 4-aminoimidazole and 2-aminothiazole derivatives as potential inhibitors of SFKs.
- To investigate the binding modes of promising compounds within the SFK ATP binding site.
- To assess the antiproliferative activity of the most potent inhibitors against cancer cell lines.
Main Methods:
- Synthesis of 4-aminoimidazole and 2-aminothiazole analogues.
- In vitro kinase assays to determine inhibitory activity (Ki values) against Src, Fyn, Lyn, and Yes.
- Computational studies including molecular docking, homology modeling, and molecular dynamics simulations.
- Antiproliferative assays using SH-SY5Y and K562 cell lines.
Main Results:
- Five promising compounds were identified with inhibition constants (Ki) ranging from 90-480 nM.
- Molecular modeling provided insights into the binding interactions within the SFK ATP binding site.
- Compound 3b exhibited the most potent antiproliferative activity against the tested cancer cell lines.
Conclusions:
- Novel 4-aminoimidazole and 2-aminothiazole derivatives show potential as SFK inhibitors.
- Compound 3b emerged as a highly active inhibitor with significant antiproliferative effects.
- These findings support the development of targeted therapies against SFK-driven cancers.
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