posted on 2021-02-10, 13:03authored byPrasanna 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
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.