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

Bioorg Med Chem Lett. 2019 Sep 1;29(17):2455-2458. doi: 10.1016/j.bmcl.2019.07.031. Epub 2019 Jul 19.

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.

Keywords: ADCs; Antibody-drug conjugates; DNA alkylation; Indolinobenzodiazepines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / chemistry*
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA / metabolism
  • Drug Design*
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use
  • Mice
  • Mice, SCID
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Alkylating Agents
  • Antibodies, Monoclonal
  • Immunoconjugates
  • DNA