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.
代谢酶与癌症驱动转录因子在肿瘤细胞中常过度表达，其暴露的半胱氨酸残基易受化学修饰。本综述探讨了半胱氨酸烷基化作为癌症治疗策略，重点关注姜黄素和堆心菊内酯等迈克尔受体与转录因子NF-κB、STAT3及HIF-1α的相互作用。通过AutoDockFR进行的分子对接研究揭示了不同的结合亲和力：姜黄素与STAT3和NF-κB呈现强相互作用，而堆心菊内酯对STAT3和HIF-1α表现出高亲和力。合成化合物如STAT3-IN-1和CDDO-Me在多数靶点中显示出更优的结合能力，但CDDO-Me与HIF-1α的结合例外，提示其存在独特的结构不相容性。天然产物如花姜酮和伞形酮表现出中等活性，而帕博西尼则凸显了合成药物的优势。这些结果强调了配体-受体结构互补性的重要性，尤其对于HIF-1α受限的结合位点，堆心菊内酯的末端迈克尔受体系统被证明是最优选择。研究结果主张整合计算与实验方法开发半胱氨酸靶向疗法，在合成药物的精确性与天然产物的多功能性之间取得平衡，以制定适应具体情境的癌症治疗策略。
Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer
肿瘤(癌症)患者之家