Design and Synthesis of Isoquinolidinobenzodiazepine Dimers, a Novel Class of Antibody-Drug Conjugate Payload.

Abstract

Antibody-drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D211), a new class of PBD dimer family of DNA damaging payloads. We have successfully synthesized all three IQB stereoisomers, experimentally showed that the purified (S,S)-D211 isomer is functionally more active than (R,R)-D221 and (S,R)-D231 isomers by >50,000-fold and ∼200-fold, respectively. We also synthesized a linker-payload (D212) that uses (S,S)-D211 payload with a cathepsin cleavable linker, a hydrophilic PEG8 spacer, and a thiol reactive maleimide. In addition, homogeneous ADCs generated using D212 linker-payload exhibited ideal physicochemical properties, and anti-CD33 ADC displayed a robust target-specific potency on AML cell lines. These results demonstrate that D212 linker-payload described here can be utilized for developing novel ADC therapeutics for targeted cancer therapy.

• Authors: Sean W Smith, Vasu Jammalamadaka, Dmitry Borkin, Jianyu Zhu, Sylvia J Degrado, Jennifer Lu, Jianqing Huang, Ying-Ping Jiang, Nareshkumar Jain, Jagath R Junutula
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 9 Issue 1 Pg. 56-60 (Jan 11 2018) ISSN: 1948-5875 [Print] United States
• PMID: 29348812 (Publication Type: Journal Article)