Design, synthesis and antitumor evaluation of a novel nectin-4 targeting bicyclic toxin conjugate

Jia-Ning Gu; Feng Liu; Yun-Song Song; Hai-Feng Ding; Xiang-Yang Feng; Xian-Li Ma; Yang-Qing Huang; Ye Zhang

doi:10.1016/j.bmcl.2025.130306

Design, synthesis and antitumor evaluation of a novel nectin-4 targeting bicyclic toxin conjugate

Bioorg Med Chem Lett. 2025 Jun 10:127:130306. doi: 10.1016/j.bmcl.2025.130306. Online ahead of print.

Authors

Jia-Ning Gu¹, Feng Liu², Yun-Song Song³, Hai-Feng Ding³, Xiang-Yang Feng³, Xian-Li Ma⁴, Yang-Qing Huang⁵, Ye Zhang⁶

Affiliations

¹ Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Jiangsu 215123, China; Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University Jiangsu 215123, China; Bright Gene Bio-Medical Technology Co., Ltd., Suzhou 215123, China.
² Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Jiangsu 215123, China; Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University Jiangsu 215123, China.
³ Bright Gene Bio-Medical Technology Co., Ltd., Suzhou 215123, China.
⁴ Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541149, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China.
⁵ Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University Jiangsu 215123, China; Bright Gene Bio-Medical Technology Co., Ltd., Suzhou 215123, China; Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541149, China. Electronic address: yqhuang@bright-gene.com.
⁶ Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541149, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China. Electronic address: zhangye@glmc.edu.cn.

PMID: 40505992
DOI: 10.1016/j.bmcl.2025.130306

Abstract

A Nectin-4 targeting bicyclic toxin conjugate (BTC) BGC1614 was designed, synthesized and evaluated as an antitumor agent. Fluorescence-activated cell sorting (FACS) assay results indicated that BGC1614 exhibited selective and strong binding to Nectin-4-expressing cells in comparison with the clinical drug BT8009. Surface plasmon resonance (SPR) test showed that the equilibrium dissociation constants (K_D) for BT8009 and BGC1614 were 3.219 ± 0.412 × 10^-7 M and 3.859 ± 0.287 × 10^-7 M, respectively, indicating that BGC1614 exhibited similar target engagement capability with Nectin-4 compared to BT8009. In vivo antiproliferative activity assay results showed that BGC1614 (0.12 μM/kg) exhibited better antiproliferative activity than BT8009 (0.12 μM/kg, inhibition rate (IR) 87.6 %) in PC-3 (human prostate cancer cell) model with IR of 96.3 %, while BGC1614 (0.36 μM/kg) displayed similar inhibition with BT8009 (0.36 μM/kg, IR 72.7 %) in N87 (human gastric cancer cell) model with IR of 70.1 %, demonstrating that BGC1614 exhibited better antitumor effect in the same molar concentration in PC-3 model. In addition, BGC1614 was well-tolerated in efficacious doses in the nude model assays, while the pharmacokinetic (PK) parameters of BGC1614 were comparable to that of BT8009.

Keywords: Antitumor activity; Bicyclic toxin conjugate; Nectin-4 targeting; Peptide-drug conjugate.