Gabriele Bassi; Nicholas Favalli; Christian Pellegrino; Yuichi Onda; Jörg Scheuermann; Samuele Cazzamalli; Markus G. Manz; Dario Neri
J. Med. Chem., 2021, 64(21), 15799-15809
https://doi.org/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.