α,β-Unsaturated carbonyl-based anticancer agents targeting cysteine residues.

The α,β-unsaturated carbonyl motif serves as an essential pharmacophore mediating the covalent modification of cysteine residues through Michael addition, thereby driving the biological activity of numerous natural products and targeted therapeutic agents. This review delineates the chemical rationale of the α,β-unsaturated carbonyl moiety as a soft electrophile and highlights its key applications in anticancer therapy in two areas: (1) as a warhead in covalent kinase inhibitors (e.g., targeting KRAS G12C, EGFR, and BTK) and (2) as electrophilic modulators of the Keap1-Nrf2 pathway via cysteine modification. Additionally, we summarize the identified protein targets of representative natural anticancer products (e.g., parthenolide and celastrol) that possess this functional moiety. Furthermore, we discuss related challenges, including off-target reactivity, and underscore emerging strategies aimed at improving selectivity. By integrating mechanistic insights with translational advances, this review offers a comprehensive perspective on α,β-unsaturated carbonyl compounds and establishes a framework for mechanism-of-action studies and rational exploitation in drug development.