Discovery of highly selective and potent CYP1B1 inhibitors for overcoming paclitaxel resistance in A549/Taxol cells.

Recent studies have demonstrated that CYP1B1 plays a crucial role in tumor drug resistance. Paclitaxel, a first-line chemotherapeutic agent for solid tumors such as non-small cell lung cancer, often encounters limitations in clinical efficacy due to drug resistance. Notably, CYP1B1 is significantly upregulated in paclitaxel-resistant cells, and its inhibition has been shown to effectively enhance the sensitivity of these resistant cells to paclitaxel. Our research group previously identified W-1, a key intermediate of Fexuprazan, as an inhibitor of CYP1B1 (IC50 = 0.16 μM). Building upon this lead compound, we designed and synthesized 52 target compounds through structural optimization. Systematic screening yielded multiple highly active and selective CYP1B1 inhibitors. Among these, the preferred compound C27 exhibited an IC50 value of 1.47 nM against CYP1B1 and demonstrated high selectivity over six major CYP isoforms. In the A549/Taxol drug-resistant cell model, C27 significantly enhanced the inhibitory effect of paclitaxel on the proliferation of resistant cells and effectively inhibited tumor cell migration and invasion. Pharmacokinetic studies revealed that C27 displayed good plasma stability and liver microsomal stability, with observable systemic exposure following both oral and intravenous administration in mice.