Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads
Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads
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DOI：
10.1016/j.bmcl.2017.10.028
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发表时间：
2017-12-01
影响因子：
2.7
通讯作者：
Gangwar, Sanjeev
中科院分区：
文献类型：
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作者：
Donnell, Andrew F.;Zhang, Yong;Gangwar, Sanjeev
设计并评价大环吡咯并苯并二氮杂卓二聚体用作抗体-药物缀合物有效载荷。初步的结构-活性探索确定，与非大环类似物相比，大环化可以增加PBD二聚体的效力。进一步的优化克服了活性限制性溶解度问题，导致化合物对几种癌细胞系具有高效（皮摩尔）活性。用抗间皮素缀合物证明了高水平的体外效力和特异性。(C)2017爱思唯尔有限公司版权所有
Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate. (C) 2017 Elsevier Ltd. All rights reserved.