Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs). Issue 17 (1st September 2019)

• Record Type: Journal Article
• Authors: Reid, Emily E.; Archer, Katie E.; Shizuka, Manami; McShea, Molly A.; Maloney, Erin K.; Ab, Olga; Lanieri, Leanne; Wilhelm, Alan; Ponte, Jose F.; Yoder, Nicholas C.; Chari, Ravi V.J.; Miller, Michael L.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 17(2019)
• Page Start: 2455
• Page End: 2458
• Publication Date: 2019-09-01
• Subjects: Antibody-drug conjugates -- DNA alkylation -- ADCs -- Indolinobenzodiazepines; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.07.031
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 .