Specific Inhibitor of Placental Alkaline Phosphatase Isolated from a DNA-Encoded Chemical Library Targets Tumor of the Female Reproductive Tract

  • J Med Chem. 2021 Nov 11;64(21):15799-15809. doi: 10.1021/acs.jmedchem.1c01103.
Gabriele Bassi  1 ,  Nicholas Favalli  1 ,  Christian Pellegrino  1  2 ,  Yuichi Onda  1 ,  Jörg Scheuermann  1 ,  Samuele Cazzamalli  3 ,  Markus G Manz  2 ,  Dario Neri  1
Affiliations
  • 1. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
  • 2. Department of Medical Oncology and Hematology, University Hospital Zürich and University of Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.
  • 3. Philochem AG, Libernstrasse 3, 8112 Otelfingen, Switzerland.
PMID: 34709820 DOI: 10.1021/acs.jmedchem.1c01103
Abstract

Placental Alkaline Phosphatase (PLAP) is an abundant surface antigen in the malignancies of the female reproductive tract. Nevertheless, the discovery of PLAP-specific small organic ligands for targeting applications has been hindered by ligand cross-reactivity with the ubiquitous tissue non-specific Alkaline Phosphatase (TNAP). In this study, we used DNA-encoded chemical libraries to discover a potent (IC50 = 32 nM) and selective PLAP inhibitor, with no detectable inhibition of TNAP activity. Subsequently, the PLAP ligand was conjugated to fluorescein; it specifically bound to PLAP-positive tumors in vitro and targeted cervical Cancer in vivo in a mouse model of the disease. Ultimately, the fluorescent derivative of the PLAP inhibitor functioned as a bispecific engager redirecting the killing of chimeric antigen receptor-T cells specific to fluorescein on PLAP-positive tumor cells.

Products