Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads

被引：5

作者：

Donnell, Andrew F. ^{[1
]}

Zhang, Yong ^{[1
]}

Stang, Erik M. ^{[1
]}

Wei, Donna D. ^{[1
]}

Tebben, Andrew J. ^{[1
]}

Perez, Heidi L. ^{[1
]}

Schroeder, Gretchen M. ^{[1
]}

Pan, Chin ^{[2
]}

Rao, Chetana ^{[2
]}

Borzilleri, Robert M. ^{[1
]}

Vite, Gregory D. ^{[1
]}

Gangwar, Sanjeev ^{[2
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Res & Dev, Redwood City, CA 94063 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 23期

关键词：

Antibody-drug conjugates; Pyrrolobenzodiazepines; Macrocycles; ANTITUMOR AGENTS; DESIGN; DOXORUBICIN; SJG-136; RELEASE; MODEL;

D O I：

10.1016/j.bmcl.2017.10.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5267 / 5271

页数：5

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