Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs).

Published on Sep 1, 2019in Bioorganic & Medicinal Chemistry Letters2.572
· DOI :10.1016/J.BMCL.2019.07.031
Emily E. Reid4
Estimated H-index: 4
(ImmunoGen, Inc.),
Katie E. Archer4
Estimated H-index: 4
(ImmunoGen, Inc.)
+ 9 AuthorsMichael L. Miller17
Estimated H-index: 17
(ImmunoGen, Inc.)
Abstract Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo .
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