DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody–Drug Conjugate Modality
Year: 2021
Type: article
Abstract: A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1 H -pyrrol-3-yl)benzene (“MPB”) payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the “MPB” binding component and guided structure–activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody–drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.
Source: ACS Medicinal Chemistry Letters
Authors: Prasanna Sivaprakasam, Ivar McDonald, Christiana Iwuagwu, Naidu S. Chowdari, Kevin M. Peese, David R. Langley, Heng Cheng, Michael R. Luzung, Michael A. Schmidt, Bin Zheng, Yichen Tan, Patricia Cho, Souvik Rakshit, Thirumalai Lakshminarasimhan, Sivakrishna Guturi, Kishorekumar Kanagavel, Umamaheswararao Kanusu, Ankita G. Niyogi, Somprabha Sidhar, Rajappa Vaidyanathan, Martin D. Eastgate, Srikanth Kotapati, Madhura Deshpande, Chin Pan, Pina M. Cardarelli, Chunshan Xie, Chetana Rao, Patrick Holder, Ganapathy Sarma, Gregory Vite, Sanjeev Gangwar
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W3128446029