Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer.

Metabolic enzymes and cancer-driving transcriptions factors are often overexpressed in neoplastic cells, and their exposed cysteine residues are amenable to chemical modification. This review explores cysteine alkylation as a cancer treatment strategy, focusing on Michael acceptors like curcumin and helenalin, which interact with transcription factors NF-κB, STAT3 and HIF-1α. Molecular docking studies using AutoDockFR revealed distinct binding affinities: curcumin showed strong interactions with STAT3 and NF-κB, while helenalin exhibited high affinity for STAT3 and HIF-1α. Synthetic compounds like STAT3-IN-1 and CDDO-Me demonstrated superior binding in most targets, except for CDDO-Me with HIF-1α, suggesting unique structural incompatibilities. Natural products such as zerumbone and umbelliferone displayed moderate activity, while palbociclib highlighted synthetic-drug advantages. These results underscore the importance of ligand-receptor structural complementarity, particularly for HIF-1α's confined binding site, where helenalin's terminal Michael acceptor system proved optimal. The findings advocate for integrating computational and experimental approaches to develop cysteine-targeted therapies, balancing synthetic precision with natural product versatility for context-dependent cancer treatment strategies.