Migliorini Francesca, Ciamarone Andrea, Dakhel Plaza Sheila, Georgiev Tony, Mascellani Marta, Sabato Emanuela, Vistoli Giulio, Biancofiore Ilaria, Favalli Nicholas, Puca Emanuele, Oehler Sebastian, Neri Dario, Cazzamalli Samuele
Philochem AG, Otelfingen, CH-8112, Switzerland.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, I-40126, Italy.
Adv Sci (Weinh). 2025 Sep;12(35):e05351. doi: 10.1002/advs.202505351. Epub 2025 Jun 29.
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.
DNA编码化学文库（DELs）是药物发现的强大工具，能够针对具有药学意义的靶蛋白对大量小分子文库进行高通量筛选。本文描述了两种新的DELs，即FM-DEL1和FM-DEL2的合成，它们分别包含7710种和5697690种化合物。这些文库是通过在苯丙氨酸中心支架上安装一组或两组构建模块构建而成。针对前列腺癌和肾细胞癌的标志物以及自然杀伤细胞表面表达的免疫靶点对FM-DELs进行筛选。通过针对这些靶点的DEL筛选获得了亲和力常数在纳摩尔范围内的高效且选择性的结合剂。针对肿瘤相关抗原的小分子配体用于开发小分子放射性药物，这些药物在全身给药后可选择性地在癌症部位积聚。
