An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors. We investigated the library for ABCG2 inhibition, for the selectivity against MDR-involved efflux pump ABCB1 (P-gp) and for toxicity. Structure activity relationship (SAR) studies revealed that, at least a phenylheteroaryl-phenylamide scaffold is necessary for observing an ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a high potency (IC₅₀ = 61 nM)), selectivity, low intrinsic toxicity and reversed the ABCG2-mediated drug resistance in presence of only 0.1 μM.

跨膜ATP结合盒转运蛋白G2（ABCG2，BCRP）在癌症组织中的过表达被认为在肿瘤的多药耐药性（MDR）中起着作用，导致化疗效率低下。因此，选择性和无毒的ABCG2抑制剂的共同给药是通过阻止ABCG2介导的细胞生长抑制药物输出来提高化疗疗效的一种有前途的策略。在本研究中，我们设计了一个包含38个新化合物的小型文库，这些新化合物包含具有几个（生物立体异构）部分的杂芳基-苯基骨架和十二个新的前体。我们调查了ABCG2抑制，针对MDR参与的外排泵ABCB1（P-gp）的选择性和毒性的库。结构活动关系（SAR）研究表明，为了观察ABCG2抑制，至少需要苯基杂芳基-苯基酰胺支架。4-甲氧基N-（2-（2-（6-甲氧基-吡啶-3-基）-2 H-四唑-5-基）苯基）苯甲酰胺（43）显示出高效力（IC ₅₀  = 61 nM））给出，选择性，低的内在在只有0.1μM的情况下可降低毒性并逆转ABCG2介导的耐药性