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

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.