Aim: The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin. Materials & methods: The target compounds (3a-c, 4a-c and 5a-c) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs). Results: Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound 4b possessed the highest potency; however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and six pockets and tubulin polymerization protein. Conclusion: Compound 4b could be considered a good antitumor candidate to go further into in vivo and clinical studies.
Antineoplastic Agents , Histone Deacetylase Inhibitors , Histone Deacetylase Inhibitors/chemistry , Tubulin/metabolism , Structure-Activity Relationship , Tubulin Modulators/pharmacology , Tubulin Modulators/chemistry , Antineoplastic Agents/chemistry , Histone Deacetylases/metabolism , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor
FAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in which the kinase has been implicated in promoting metastases. Consequently, designing and developing potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as a promising tool in our armamentarium for treating diverse cancers. This review comprehensively summarizes the different classes of synthetically derived compounds that have been reported as potent FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed to slow down the emergence of drug resistance is discussed.
Antineoplastic Agents/chemistry , Biomarkers, Tumor/antagonists & inhibitors , Focal Adhesion Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Amino Acid Sequence , Antineoplastic Agents/pharmacology , Binding Sites , Drug Design , Heterocyclic Compounds/chemistry , Humans , Models, Molecular , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/pharmacology , Signal Transduction , Structure-Activity Relationship
