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Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads |
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| Authors: | Andrew F. Donnell Yong Zhang Erik M. Stang Donna D. Wei Andrew J. Tebben Heidi L. Perez Gretchen M. Schroeder Chin Pan Chetana Rao Robert M. Borzilleri Gregory D. Vite Sanjeev Gangwar |
| Affiliation: | 1. Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USA;2. Bristol-Myers Squibb Research & Development, Redwood City, CA 94063, USA |
| 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. |
| Keywords: | Antibody-drug conjugates Pyrrolobenzodiazepines Macrocycles |
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