Authors
Jiajun Xie, Yalong Li, Fengyuan Pan, Yifan Wang, Wei Lu, Bo Wang, Shulei Zhu, Juan Zhang
Published in
Journal of medicinal chemistry. Volume 69. Issue 17. Pages 20213-20229. Sep 10, 2026.
Abstract
Camptothecin derivatives, exemplified by DXd, are a dominant class of payloads for antibody-drug conjugates (ADCs). Herein, we describe the design and synthesis of H2, a novel homocamptothecin featuring a simplified hydroxybutyl structure that circumvents the complex assembly of the F-ring. H2 exhibits superior hydrolytic stability, while maintaining potent intrinsic cytotoxicity. In vitro, the H2-conjugated ADC candidates, Tras-L-H2 and Tras-TL-H2, demonstrated robust bystander killing effect and potent antiproliferative activity, similar to that observed with T-DXd. Importantly, these candidates exhibited noninferior antitumor efficacy to that of T-DXd in JIMT-1 xenograft model. These findings demonstrate the therapeutic utility of the seven-membered homocamptothecin scaffold and identify H2 as a promising candidate for next-generation ADC payloads.
PMID:
42720475
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.
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