Design, Synthesis, and Structure–Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody–Drug Conjugates

• Published in: Journal of medicinal chemistry 2020-11, Vol.63 (22), p.13913-13950
• Main Authors: Chowdari, Naidu S, Zhang, Yong, McDonald, Ivar, Johnson, Walter, Langley, David R, Sivaprakasam, Prasanna, Mate, Robert, Huynh, Tram, Kotapati, Srikanth, Deshpande, Madhura, Pan, Chin, Menezes, Daniel, Wang, Yichong, Rao, Chetana, Sarma, Ganapathy, Warrack, Bethanne M, Rangan, Vangipuram S, Mei-Chen, Sung, Cardarelli, Pina, Deshpande, Shrikant, Passmore, David, Rampulla, Richard, Mathur, Arvind, Borzilleri, Robert, Rajpal, Arvind, Vite, Gregory, Gangwar, Sanjeev
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Benzodiazepines - chemistry; Benzodiazepines - metabolism; Cell Proliferation; Drug Design; Female; G(M1) Ganglioside - analogs & derivatives; G(M1) Ganglioside - immunology; GPI-Linked Proteins - immunology; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Mice; Mice, SCID; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - pathology; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Structure-Activity Relationship; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01385

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure–activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine–citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 μmol/kg).