DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody–Drug Conjugate Modality
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 id...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2021-03, Vol.12 (3), p.404-412 |
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| creator | Sivaprakasam, Prasanna McDonald, Ivar Iwuagwu, Christiana Chowdari, Naidu S Peese, Kevin M Langley, David R Cheng, Heng Luzung, Michael R Schmidt, Michael A Zheng, Bin Tan, Yichen Cho, Patricia Rakshit, Souvik Lakshminarasimhan, Thirumalai Guturi, Sivakrishna Kanagavel, Kishorekumar Kanusu, Umamaheswararao Niyogi, Ankita G Sidhar, Somprabha Vaidyanathan, Rajappa Eastgate, Martin D Kotapati, Srikanth Deshpande, Madhura Pan, Chin Cardarelli, Pina M Xie, Chunshan Rao, Chetana Holder, Patrick Sarma, Ganapathy Vite, Gregory Gangwar, Sanjeev |
| description | 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. |
| doi_str_mv | 10.1021/acsmedchemlett.0c00578 |
| format | Article |
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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. 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| source | EZB-FREE-00999 freely available EZB journals; PubMed Central; American Chemical Society Journals |
| subjects | Letter |
| title | DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody–Drug Conjugate Modality |
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