Novel Inhibitors of BCRP and P-Glycoprotein in Cancer Treatment

Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are ATP-binding cassette transporters involved in clinically relevant drug-drug interactions (DDI). This study aimed to identify new BCRP and P-gp inhibitors among used in the treatment of cancer, as the inhibition by many commonly used anticancer and supportive care drugs remains unclear. A total of 133 drugs were screened at 50 µM for inhibition of BCRP and P-gp using a transport assay with BCRP or P-gp-expressing membrane vesicles. Following initial screening, 50% inhibitory concentrations (IC50) were predicted, and the most potent inhibitors were selected for experimental IC50 determination. The risks of intestinal and systemic inhibition of BCRP and P-gp were assessed by comparing the estimated intestinal concentration (I2; dose/250 ml) and maximum plasma concentration (I1) to the IC50 values. If the I2/IC50 ratio surpassed 10 or the I1/IC50 ratio exceeded 0.1, in vivo inhibition was considered possible. Mechanistic static modelling was then utilized to assess the risk of a pharmacokinetic DDI in humans. Following initial screening, 24 and 23 drugs were selected for the determination of IC50 values for BCRP and P-gp, respectively. Of the investigated compounds, cabozantinib (IC50 of 0.65 µM), midostaurin (0.69 µM), and entrectinib (5.8 µM) showed the strongest inhibition of BCRP. Nilotinib (1.0 µM), osimertinib (2.0 µM), and abemaciclib (2.4 µM) showed the strongest inhibition of the P-gp. The highest I2/IC50 ratios for BCRP were observed for mitotane (6190), cabozantinib (1730), and abiraterone (831). For P-gp, the highest I2/IC50 ratios were observed for nilotinib (2880), pazopanib (1580), and mitotane (1480). These compounds might therefore inhibit BCRP or P-gp in the intestine. The highest I1/IC50 ratios for BCRP were observed for doxorubicin (8.2), etoposide (2.8), and fosaprepitant (0.84). For P-gp, the highest I1/IC50 ratios were observed for amscarine (1.6), vinorelbine (0.55), and fosaprepitant (0.50). These compounds might therefore inhibit systemic BCRP or P-gp. Mechanistic static model for BCRP inhibitors suggested that cabozantinib, midostaurin, and apalutamide could almost fully inhibit intestinal BCRP, increasing the exposure to concomitantly administered rosuvastatin by 94%, 89%, and 83%, respectively. Similarly, mechanistic static model for P-gp inhibitors suggested that sorafenib, cabozantinib, and nilotinib could almost fully inhibit intestinal P-gp, increasing the exposure to concomitantly administered dabigatran etexilate by 124%, 123%, and 115%, respectively. Our findings identified multiple novel BCRP and P-gp inhibitors, which may cause transporter-mediated DDIs in cancer treatment. Clinical DDI studies are warranted to investigate the potential interactions in humans. Citation Format: Martina Timonen,Feng Deng,Mikko Niemi. Novel inhibitors of BCRP and P-gp found among drugs used in the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3154.