| Literature DB >> 33738068 |
Prasanna Sivaprakasam1, Ivar McDonald2, Christiana Iwuagwu2, Naidu S Chowdari3, Kevin M Peese2, David R Langley1, Heng Cheng3, Michael R Luzung4, Michael A Schmidt4, Bin Zheng4, Yichen Tan4, Patricia Cho4, Souvik Rakshit5, Thirumalai Lakshminarasimhan5, Sivakrishna Guturi5, Kishorekumar Kanagavel5, Umamaheswararao Kanusu5, Ankita G Niyogi5, Somprabha Sidhar5, Rajappa Vaidyanathan5, Martin D Eastgate4, Srikanth Kotapati6, Madhura Deshpande6, Chin Pan7, Pina M Cardarelli7, Chunshan Xie8, Chetana Rao6, Patrick Holder6, Ganapathy Sarma6, Gregory Vite9, Sanjeev Gangwar3.
Abstract
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.Entities:
Year: 2021 PMID： 33738068 PMCID： PMC7957924 DOI： 10.1021/acsmedchemlett.0c00578
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345