학술논문
Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs).
Document Type
Academic Journal
Author
Reid EE; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Archer KE; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Shizuka M; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; McShea MA; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Maloney EK; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Ab O; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Lanieri L; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Wilhelm A; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Ponte JF; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Yoder NC; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Chari RVJ; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States.; Miller ML; ImmunoGen, Inc., 830 Winter Street, Waltham, MA 02451, United States. Electronic address: michael.miller@immunogen.com.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
Subject
Language
English
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.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
(Copyright © 2019 Elsevier Ltd. All rights reserved.)