Synthesis and Evaluation of Camptothecin Antibody–Drug Conjugates

Published on Sep 6, 2019in ACS Medicinal Chemistry Letters3.975
· DOI :10.1021/ACSMEDCHEMLETT.9B00301
Wei Li3
Estimated H-index: 3
(ImmunoGen, Inc.),
Karen Veale4
Estimated H-index: 4
(ImmunoGen, Inc.)
+ 15 AuthorsWayne C. Widdison15
Estimated H-index: 15
(ImmunoGen, Inc.)
Antibody–drug conjugates (ADCs) that incorporate the exatecan derivative DXd in their payload are showing promising clinical results in solid tumor indications. The payload has an F-ring that also contains a second chiral center, both of which complicate its synthesis and derivatization. Here we report on new camptothecin-ADCs that do not have an F-ring in their payloads yet behave similarly to DXd-bearing conjugates in vitro and in vivo. This simplification allows easier derivatization of camptothecin A and B rings for structure–activity relationship studies and payload optimization. ADCs having different degrees of bystander killing and the ability to release hydroxyl or thiol-bearing metabolites following peptide linker cleavage were investigated.
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