Develop selective inhibitors of drug-metabolizing enzymes CYP3A4/5 to improve cancer drug efficacy and reduce drug toxicity and resistance

Background: The human cytochrome P450 (CYP) CYP3A4 and CYP3A5 enzymes metabolize more than half of marketed drugs. They share high structural substrate similarity are often studied together as CYP3A4/ 5. However, they preferentially different clinically prescribed Moreover, the differential distribution expression levels in both normal diseased tissues can aggravate toxicity induce resistance during treatment. Therefore, selective inhibitors needed to distinguish their roles serve starting points for potential therapeutic development. Materials methods: We used biochemical cell-based assays high-throughput screening discover characterize inhibitors. X-ray crystallography unravel basis inhibition. Results: discovered clobetasol propionate first inhibitor reported crystal structure complex with propionate. Supported by structure-guided mutagenesis analyses, CYP3A5-clobetasol showed that a unique conformation F–F′ loop enables binding CYP3A5, thus proving Based on these results we performed large-scale identify additional suitable chemical optimization. Conclusions: It is feasible selectively inhibit highly homologous enzymes, chemically validating targets development therapeutics improve drug efficacy while reducing No conflict interest.