2. Academic Validation
  3. Coibamide Analogue as a Novel-Class Payload for Antibody-Drug Conjugate

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

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.

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