Open AccessDNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody–Drug Conjugate Modality
Author(s) -
Prasanna Sivaprakasam,
Ivar M. McDonald,
Christiana Iwuagwu,
Naidu S. Chowdari,
Kevin M. Peese,
David R. Langley,
Heng Cheng,
Michael R. Luzung,
Michael A. Schmidt,
Bin Zheng,
Yee Sun 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 Chen Pan,
Pina M. Cardarelli,
Chunshan Xie,
Chetana Rao,
Patrick G. Holder,
Ganapathy N. Sarma,
Gregory D. Vite,
Sanjeev Gangwar
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00578
Subject(s) - conjugate , antibody drug conjugate , chemistry , linker , antibody , monoclonal antibody , conjugated system , immunotoxin , in vitro , cancer research , combinatorial chemistry , biochemistry , cytotoxicity , computer science , biology , immunology , operating system , mathematical analysis , polymer , mathematics , organic chemistry
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.