AbstractThe role of ATP‐binding cassette (ABC) transporter‐mediated multidrug resistance (MDR) in anti‐cancer therapy is often challenging, frequently leading to inefficiency of treatments. Cancer cells exploit efflux transporters, like the breast cancer resistance protein (BCRP, ABCG2), to secrete chemotherapeutic substances. In this study, an N‐phenyl‐2‐carboranylquinazolin‐4‐amine (8) was designed as inorganic‐organic hybrid BCRP inhibitor. In particular, the ABCG2‐transporter inhibitor‐prominent scaffold N‐phenylquinazolin‐4‐amine was combined with a boron−carbon cluster (carborane) moiety. Introducing a carborane at 2‐position of the quinazoline scaffold resulted in an increased inhibitory activity towards human ABCG2 (hABCG2) compared to its recently published regioisomer N‐carboranyl‐2‐phenyl‐quinazolin‐4‐amine. The carboranylquinazoline 8 further showed the ability to reverse hABCG2‐mediated drug resistance in MDCKII‐hABCG2 cells by lowering the IC50 value of the BCRP‐substrate mitoxantrone, similar to the standard reference and strong inhibitor Ko143, without exhibiting intrinsic toxicity in the lower micromolar ranges. These results make compound 8 a promising scaffold for the design of further BCRP inhibitors.