Isatin as a privileged scaffold for kinase inhibition: recent advances in anti-cancer research

Protein kinases are key therapeutic targets in anticancer drug discovery due to their central roles in regulating cell proliferation, survival, and signaling pathways. Among diverse heterocyclic scaffolds, isatin (indole-2,3-dione) has emerged as a privileged framework for the development of potent kinase inhibitors due to its structural versatility and favorable interaction profile within binding pockets. This review provides a comprehensive overview of recent advances in isatin-based kinase inhibitors, highlighting their design strategies, structure-activity relationships (SAR), and key molecular determinants of potency and selectivity. Particular emphasis is placed on structural optimization at the N-1 and C-5/C-7 positions, as well as hybridization with heterocyclic pharmacophores has yielded compounds with nanomolar inhibitory activity against clinically relevant targets, including cyclin dependent kinases (CDKs), vascular-endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and other kinases. In addition, ligand-kinase interactions are critically analyzed, with focus on hinge-region hydrogen bonding and hydrophobic complementarity within the ATP-binding site. Computational approaches, including molecular docking studies, are integrated to rationalize binding modes and support SAR interpretations. Collectively, this review underscores isatin as a versatile and promising scaffold for the rational design of next generation multitarget kinase inhibitors with potential applications in anticancer therapy.