CYP1B1 Enzymatic Activity Promotes Non-Small Cell Lung Cancer Metastasis: Antimetastatic Effects of Novel CYP1B1 Inhibitors.

Metastasis represents a major cause of chemotherapy failure in non-small cell lung cancer (NSCLC). To explore the role of CYP1B1 enzymatic activity in NSCLC metastasis, we established A549 and H460 cells overexpressing wild-type CYP1B1, an activity-enhanced variant (L432V), and an activity-reduced variant (N203S). CYP1B1 did not affect cell proliferation but promoted migration and invasion, with the extent of these effects being associated with CYP1B1 enzymatic activity. We then designed and synthesized a series of CYP1B1 inhibitors. Compound G26 exhibited high selectivity over other CYP isoforms (IC50 = 5.33 nM), showed favorable microsomal metabolic stability with species differences, significantly inhibited migration and invasion in A549 and H460 cells, exhibited moderate oral bioavailability in SD rats (F = 20.7%), and showed a favorable safety profile in mice.