Coibamide Analogue as a Novel-Class Payload for Antibody-Drug Conjugate

  • J Med Chem. 2026 Mar 12;69(5):5691-5702. doi: 10.1021/acs.jmedchem.5c02941.
Hui Tian  1  2 ,  Wencong Pan  3 ,  Huaihuai Shi  2 ,  Ximing Shao  2 ,  Jingjing Sun  3 ,  Jiaming Liang  2 ,  Bichun Chen  2 ,  Binghua Cheng  2 ,  Ke Liu  2 ,  Guiyang Yao  3 ,  Wu Su  3 ,  Hongchang Li  2  4 ,  Lijing Fang  2  4
Affiliations
  • 1. Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518805, China.
  • 2. Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
  • 3. Center for Innovative Drug Discovery, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou 511462, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 41718583 DOI: 10.1021/acs.jmedchem.5c02941
Abstract

Although antibody-drug conjugates (ADCs) have made substantial progress as targeted therapies, the range of suitable ADC Payloads remains limited. In this study, the highly N-methylated cyclodepsipeptide [MeAla3-MeAla6]-coibamide (CA) was selected as a novel toxin for ADC construction due to its potent toxicity and unique mechanism of action. Using a quaternary ammonium salt approach, two linker-payload variants, MC-VA-PAB-CA and MC-GGFG-PAB-CA, with distinct Cathepsin B (CTB)-cleavable linkers, were synthesized and assessed. Among them, MC-GGFG-PAB-CA demonstrated higher enzyme-responsive cleavage efficiency and superior plasma stability and was selected for conjugation with the epidermal growth factor receptor (EGFR) antibody cetuximab (Ctx), resulting in the formation of Ctx-CA. This conjugate exhibited EGFR-dependent antitumor activity, a pronounced "bystander killing effect", and a significant tumor suppression effect in mouse models. Furthermore, the applicability of this conjugation strategy was confirmed through validation with the HER2 antibody. These findings suggest that CA is a promising weapon for next-generation ADCs.

Products