Nicotinonitriles-based therapeutics as versatile pharmacophores in rational anticancer drug design

Nicotinonitriles (3-cyanopyridine-based compounds) are emerging as privileged frameworks in rational anticancer drug discovery due to their distinctive electronic properties, metabolic stability, and diverse pharmacological profiles. This review discusses recent developments in nicotinonitrile-derived agents as effective kinase inhibitors of EGFR, VEGFR-2, HER2, CDKs, c-Met, BRAF, and PIM kinases, among others. By discussing mono-, bi-, and multi-target inhibitors, the mechanisms of action are reviewed, with adaptations to induce apoptosis, arrest the cell cycle, and reverse drug resistance. Many clinical and preclinical candidates are nanomolar to sub-micromolar in equipotency across multiple cancer models. The substitution at the core of nicotinonitrile improves targeted selectivity, drug-like properties, and the safety profile, and is a key toward next-generation anticancer agents. Moreover, the review presents information on enzyme-mediated inhibition, hybrid construction, and molecular docking that strengthen the scaffold's potential for ecotoxicological pipelines. Overall, nicotinonitrile-based derivatives seem to be an attractive nucleus for multi-target drug discovery, with a broad therapeutic spectrum in cancer management.