Altered redox regulation in cancer cells represents a chemical vulnerability that can be targeted by small-molecule redox modulators that have shown therapeutic promise in animal xenograft models and clinical trials. Based on the emerging role of pro-oxidant therapeutics in anti-cancer intervention, we hypothesized that drug-like molecules containing a reactive Michael acceptor pharmacophore with attenuated electrophilicity may be developed into experimental redox chemotherapeutics. Using gene expression array analysis and luciferase-based transcriptional reporter profiling (Nrf2, NFkappaB) of the cellular electrophilic stress response we identified Michael acceptor pharmacophores that impart anti-cancer activity at doses devoid of systemic toxicity. 2,6-dichlorophenolindophenol (DCPIP) was identified as a glutathione-directed Michael acceptor targeting metastatic A375 melanoma in vivo. Proteomic identification of molecular targets in melanoma modulated by Michael adduction is ongoing. Moreover, cinnamaldehyde-derived Nrf2 activators are now in preclinical development for skin cancer chemoprevention. (Support: NIH (R01CA122484); ACS, predoctoral fellowship (CC), Division of Medicinal Chemistry, sponsored by Novartis).

Designing attenuated Michael acceptors as experimental redox chemotherapeutics targeting skin cancer

240th National Meeting (2010)

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