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

  • Bioorg Med Chem Lett. 2025 Nov 1:127:130306. doi: 10.1016/j.bmcl.2025.130306.
Jia-Ning Gu  1 ,  Feng Liu  2 ,  Yun-Song Song  3 ,  Hai-Feng Ding  3 ,  Xiang-Yang Feng  3 ,  Xian-Li Ma  4 ,  Yang-Qing Huang  5 ,  Ye Zhang  6
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: [email protected].
  • 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: [email protected].
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 (KD) 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.
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