Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs).

Published on Jul 22, 2019in ACS Medicinal Chemistry Letters3.975
· DOI :10.1021/ACSMEDCHEMLETT.9B00254
Katie E. Archer4
Estimated H-index: 4
(ImmunoGen, Inc.),
Emily E. Reid4
Estimated H-index: 4
(ImmunoGen, Inc.)
+ 12 AuthorsMichael L. Miller17
Estimated H-index: 17
(ImmunoGen, Inc.)
Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody–drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). These ADCs possess linkers that have been incorporated into a central substituted phenyl spacer. Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked IGN ADCs with a wide range of in vitro potency and tolerability, which may allow us to better match an IGN with a particular target based on the potential dosing needs.
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