DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody–Drug Conjugate Modality
| Autor: | Michael A. Schmidt, Chunshan Xie, Naidu S. Chowdari, Ankita G. Niyogi, David R. Langley, Heng Cheng, Gregory D. Vite, Sivakrishna Guturi, Rajappa Vaidyanathan, Sanjeev Gangwar, Ivar M. McDonald, Kishorekumar Kanagavel, Yichen Tan, Prasanna Sivaprakasam, Souvik Rakshit, Chin Pan, Umamaheswararao Kanusu, Martin D. Eastgate, Madhura Deshpande, Somprabha Sidhar, Bin Zheng, Christiana I. Iwuagwu, Michael R. Luzung, Ganapathy Sarma, Kevin M. Peese, Thirumalai Lakshminarasimhan, Patrick G. Holder, Pina M. Cardarelli, Patricia Cho, Srikanth Kotapati, Chetana Rao |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Antibody-drug conjugate biology 010405 organic chemistry medicine.drug_class Organic Chemistry Peptide Monoclonal antibody 01 natural sciences Biochemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Drug Discovery medicine biology.protein Antibody Cytotoxicity Linker Conjugate |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-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. |
| Databáze: | OpenAIRE |
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