The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors.
The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors.
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DOI：
10.20517/cdr.2021.19
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Hrycyna CA
中科院分区：
文献类型：
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作者：
Goebel J;Chmielewski J;Hrycyna CA
三磷酸腺苷结合盒(ABC)转运体P-糖蛋白(P-gp)和ABCG2是细胞培养中对多种抗癌药物产生耐药性的多药转运体。这些发现最初在医学肿瘤界引起了极大的兴奋，因为这些转运蛋白的抑制剂有望克服癌症患者的临床多药耐药性。然而，P-gp和ABCG2抑制剂与癌症化疗药物联合使用的临床试验尚未成功，部分原因是临床试验设计存在缺陷，这是由于对所研究癌症的多药耐药(MDR)的多因素基础的分子理解不完整。该领域也因缺乏高分辨率的P-gp和ABCG2的结构信息而受到阻碍，这些信息可用于合理的基于结构的抑制剂药物设计。结构生物学的最新进展导致了ABCG2和P-gp的大量结构，这些结构更清楚地阐明了转运机制及其底物和抑制剂结合部位的多特异性。这些数据应该有助于开发更有效和更特异的两种转运蛋白的抑制剂。因此，尽管需要评估可能的药代动力学相互作用，但这些抑制剂可能在仔细选择的癌症亚类中结合化疗药物，在克服ABC依赖的多药耐药方面显示出更大的有效性。这些抑制剂的另一个可能更令人信服的用途可能是可逆地抑制内源性表达的P-gp和ABCG2，它们在各种血-组织屏障中起到保护作用。在大脑和肠道等避难所抑制这些转运蛋白可能会导致用于治疗脑癌或其他脑部疾病的化疗药物的渗透率增加，并提高这些药物的口服生物利用度。
The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture. These findings initially created great excitement in the medical oncology community, as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients. However, clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due, in part, to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance (MDR) in the cancers examined. The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors. Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites. These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters. As such, although possible pharmacokinetic interactions would need to be evaluated, these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers. Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2, which serve a protective role at various blood-tissue barriers. Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents, respectively.