Quinazoline derivatives as selective CYP1B1 inhibitors

CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid ‘O’ atom with ‘N’ atom led to the prediction that a ‘quinazoline’ scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells. We report discovery of quinazoline class of cell permeable selective CYP1B1 inhibitors. [Display omitted] •Quinazoline scaffold has been identified as a new class of CYP1B1 inhibitor.•Compound 5c showed potent inhibition of CYP1B1 with IC50 of 3 nM.•CYP1B1 inhibition has also been studied in live yeast and human cells.•Compound 5c is highly selective CYP1B1 inhibitor.•Compound 5c does not inhibit other CYPs (IC50 > 10,000 nM).