Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine–Anthracenecarboxyimide as a Payload for Antibody–Drug Conjugate

A novel series of hybrid molecules combining pyrrolobenzodiazepine
(PBD) and anthracenecarboxyimide pharmacophores were designed, synthesized,
and tested for in vitro cytotoxicity against various
cancer cell lines. The most potent compound from this series, 37b3, exhibited a subnanomolar level of cytotoxicity with
an IC50 of 0.17–0.94 nM. 37b3 induced
DNA damage and led to tumor cell cycle arrest and apoptosis. We employed 37b3 as a payload to conjugate with trastuzumab to obtain
the antibody–drug conjugate (ADC) T-PBA. T-PBA maintained its
mode of target and internalization ability of trastuzumab. We demonstrated
that T-PBA could be degraded through the lysosomal pathway to release
the payload 37b3 after internalization. T-PBA showed
a powerful killing effect on Her2-positive cancer cells in
vitro. Furthermore, T-PBA significantly inhibited tumor growth
in gastric and ovarian cancer xenograft mouse models without overt
toxicity. Collectively, these studies suggest that T-PBA represents
a promising new ADC that deserves further investigation.