Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads
Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads
复制标题
DOI：
10.1021/acs.jmedchem.9b02129
复制
发表时间：
2020-04-23
影响因子：
7.3
通讯作者：
Bennett, Gavin S.
中科院分区：
文献类型：
--
作者：
Mudd, Gemma E.;Brown, Amy;Bennett, Gavin S.
自行车是一种受限制的双环肽，代表了一种很有前途的结合方式，可用于靶向药物结合物。EphA2是一种受体酪氨酸激酶，在许多实体肿瘤中高表达，噬菌体展示屏幕鉴定了一些低纳摩尔亲和力的自行车家族。一种自行车毒素结合物(BTC)是由其中一辆自行车与有效的细胞毒素DM1通过可切割连接子衍生化而产生的。这种BTC在体内显示了很强的抗肿瘤活性，但耐受性很差，这被认为是由于糟糕的物理化学性质导致的不希望看到的肝脏摄取的结果。第二辆自行车的化学优化，以结构生物学为指导，提供了一种高亲和力、代谢稳定、物化性能改善的自行车。含有这种自行车的BTC也显示出强大的抗肿瘤活性，与最初的BTC相比，耐受性非常好。噬菌体展示选择和自行车的化学优化可以提供具有良好药理性能的有效药物结合物。
Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, a receptor tyrosine kinase highly expressed in a number of solid tumors, identified a number of Bicycle families with low nanomolar affinity. A Bicycle toxin conjugate (BTC) was generated by derivatization of one of these Bicycles with the potent cytotoxin DM1 via a cleavable linker. This BTC demonstrated potent antitumor activity in vivo but was poorly tolerated, which was hypothesized to be the result of undesired liver uptake caused by poor physicochemical properties. Chemical optimization of a second Bicycle, guided by structural biology, provided a high affinity, metabolically stable Bicycle with improved physicochemical properties. A BTC incorporating this Bicycle also demonstrated potent antitumor activity and was very well tolerated when compared to the initial BTC. Phage display selection followed by chemical optimization of Bicycles can deliver potent drug conjugates with favorable pharmaceutical properties.