Novel inhibitors of BCRP found among drugs used in the treatment of cancer.

Breast cancer resistance protein (BCRP) is an ATP-binding cassette transporter involved in clinically relevant drug-drug interactions. We aimed to identify new BCRP inhibitors among drugs used in cancer treatment. Accordingly, 133 drugs were screened at 50 µM for inhibition of BCRP using vesicular transport assay. Half-maximal inhibitory concentrations (IC50) were predicted, and compounds showing the highest inhibitory potencies relative to their systemic (I1) or intestinal (I2) concentrations were selected for experimental IC50 determination. A mechanistic static model was used to predict potential interactions with the BCRP substrate rosuvastatin in humans. Food and Drug Administration Adverse Event Reporting System (FAERS) was searched for signals of rosuvastatin-induced rhabdomyolysis during co-administration with the investigated drugs. Of the 133 drugs screened, 42 had a predicted IC50 value over 0.1×I₁ and 61 over 10×I₂, suggesting potential inhibition in humans. IC50 values were experimentally determined for 24 selected drugs. Cabozantinib and midostaurin were the strongest inhibitors, with IC50 values of 0.65 and 0.69 µM, respectively. Moreover, the model suggested that midostaurin, cabozantinib, and alpelisib could almost fully inhibit intestinal BCRP, nearly doubling rosuvastatin exposure (1.83- to 1.94-fold). Entrectinib, alpelisib, flutamide, abiraterone, and capecitabine were predicted to increase rosuvastatin exposure by 1.45- to 1.63-fold through BCRP inhibition. FAERS analysis indicated a higher frequency of rhabdomyolysis reports when abiraterone was co-administered with rosuvastatin compared with all reports without abiraterone, with a reporting odds ratio of 17.3. This study identified multiple previously unrecognized BCRP inhibitors, highlighting the potential for clinically relevant BCRP‑mediated drug-drug interactions in oncology patients.