Cytochrome P450s (CYPs) are responsible for metabolic activation of carcinogens and overexpressed in several cancers, including bladder cancer. Overexpression of CYP2A6 and 1B1 is associated with chemotherapy resistance, and silencing of CYP2A6 resulted in improved cell killing. Therefore, CYP1B1 and 2A6 proteins can be considered as therapeutic targets, and inhibition or degradation of these proteins could overcome cisplatin resistance in chemotherapy of bladder cancer. The design and synthesis of new PROTACs was conducted based on known inhibitors of CYP2A6 and CYP1B1. Conjugated groups such as thalidomide were incorporated. Thalidomide recruits cereblon (CRBN), which induces ubiquitination of the enzyme, sending it to the proteasome for degradation. To develop the Ru-based prodrugs with CYP inhibitors and Ru-based photo-PROTACs, a photocaging approach was utilized. The synthetic approaches, photochemical features, new data for inhibition and degradation of CYPs, and structure-activity relationship analysis will be presented.

Development of new PROTACs and light-activated inhibitors for cytochrome P450 (1B1, 2A6)

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