Michael addition drugs and cancer.

Some of the earliest anticancer drugs were alkylating agents, capable of covalently modifying critical cellular nucleophiles in proteins and nucleic acids. For many years, adapting another type of covalent reaction, Michael addition reactions, which involve the nucleophilic attack of a carbon nucleophile on an α,β-unsaturated carbonyl compound, have been explored in designing covalent inhibitors that selectively target cancer-related biomolecules. Numerous natural products demonstrate Michael addition properties, contributing to their bioactivity in antioxidant, anti-inflammatory and anticancer mechanisms. These compounds often interact with cellular nucleophiles, modulating redox signaling, enzyme catalysis, and stress response pathways. In the context of cancer treatments, several FDA-approved drugs, including proteostatic, EGFR and Ras inhibitors, employ Michael addition chemistry to achieve irreversible inhibition of cancer-related targets. The review emphasizes the challenges associated with these drugs, including off-target effects, toxicity, and drug resistance, but highlights some advances in medicinal chemistry that have improved selectivity and therapeutic efficacy. There are emerging covalent inhibitors that leverage Michael addition to enhance cancer treatment, underscoring the ongoing efforts to refine these compounds for clinical translation. Overall, this review examines the mechanisms, applications, and therapeutic potentials of Michael addition drugs in oncology, alongside relevant literature, and clinical findings.