Abstract
A number of new compounds containing the 4-(aminomethyl)benzamide fragment as a linker were designed and synthesized, and their biological activities were evaluated as potential anticancer agents. The cytotoxicity activity of the designed compounds was studied in two hematological and five solid cell lines in comparison with the reference drugs. Targeted structures against eight receptor tyrosine kinases including EGFR, HER-2, HER-4, IGF1R, InsR, KDR, PDGFRa, and PDGFRb were investigated. The majority of the compounds showed a potent inhibitory activity against the tested kinases. The analogues 11 and 13 with the (trifluoromethyl)benzene ring in the amide or amine moiety of the molecule were proven to be highly potent against EGFR, with 91% and 92% inhibition at 10 nM, respectively. The docking of synthesized target compounds for nine protein kinases contained in the Protein Data Bank (PDB) database was carried out. The molecular modeling results for analogue 10 showed that the use of the 4-(aminomethyl)benzamide as a flexible linker leads to a favorable overall geometry of the molecule, which allows one to bypass the bulk isoleucine residue and provides the necessary binding to the active center of the T315I-mutant Abl (PDB: 3QRJ).
Highlights
Protein kinases serve as therapeutic targets for a range of clinical indications and represent the largest category of drug targets in current clinical trials [1]
The VEGFR inhibitors target a wide spectrum of kinases, including the platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR)
We investigated the kinase selectivity of targeted compounds against eight receptor tyrosine kinases including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2 and HER4, IGF1R, InsR, kinase insert domain receptor (KDR)
Summary
Protein kinases serve as therapeutic targets for a range of clinical indications and represent the largest category of drug targets in current clinical trials [1]. The first-generation Bcr-Abl inhibitor imatinib achieved great clinical success and became the first-line drug for the treatment of chronic myeloid leukemia (CML) [2]. After the introduction of imatinib, the therapeutic armamentarium in solid malignancies was expanded by the registration of several other tyrosine kinase inhibitors (TKIs). These include the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib, the dual EGFR and human epidermal growth factor receptor (HER)-2 inhibitor lapatinib, and the VEGFR (vascular endothelial growth factor receptor) inhibitors sunitinib, sorafenib, and, recently, pazopanib. The VEGFR inhibitors target a wide spectrum of kinases, including the platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR)
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