Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads. Issue 23 (1st December 2017)

• Record Type: Journal Article
• Authors: Donnell, Andrew F.; Zhang, Yong; Stang, Erik M.; Wei, Donna D.; Tebben, Andrew J.; Perez, Heidi L.; Schroeder, Gretchen M.; Pan, Chin; Rao, Chetana; Borzilleri, Robert M.; Vite, Gregory D.; Gangwar, Sanjeev
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 23(2017)
• Page Start: 5267
• Page End: 5271
• Publication Date: 2017-12-01
• Subjects: Antibody-drug conjugates -- Pyrrolobenzodiazepines -- Macrocycles; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.10.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.