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

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).