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Phenylalanine‐Based DNA‐Encoded Chemical Libraries for the Discovery of Potent and Selective Small Organic Ligands Against Markers of Cancer and Immune Cells

Year: 2025
Type: article
Abstract: DNA-encoded chemical libraries (DELs) are powerful tools for drug discovery, enabling the high-throughput screening of vast libraries of small molecules against target proteins of pharmaceutical interest. Here, the synthesis of two new DELs, named FM-DEL1 and FM-DEL2, including 7'710 and 5'697'690 compounds, respectively is described. These libraries are constructed by installing one or two sets of building blocks on a phenylalanine central scaffold. FM-DELs are screened against markers of prostate cancer, and renal cell carcinoma, and against an immunological target expressed on the surface of natural killer cells. Highly potent and selective binders with affinity constants in the nanomolar range are obtained from DEL screenings against those targets. Small-molecule ligands against tumor-associated antigens are used to develop small-molecule radiopharmaceuticals that selectively accumulate at cancer sites after systemic administration.
DOI: 10.1002/advs.202505351
Authors: Francesca Migliorini, Andrea Ciamarone, Sheila Dakhel Plaza, Tony Georgiev, Marta Mascellani, Emanuela Sabato, Giulio Vistoli, Ilaria Biancofiore, Nicholas Favalli, Emanuele Puca, Sebastian Oehler, Dario Neri, Samuele Cazzamalli
Institutions: Philochem (Switzerland), Italian Institute of Technology, University of Bologna, University of Milan, Philogen (Italy), ETH Zurich
Language: English
Open Access status: gold
Estimated APC paid: $6,730
OpenAlex ID: W4411779132
FWCI: 1.278
Cites: 59
Cited by: 5
Related to: 10