Yuqing Deng; Jianzhao Peng; Feng Xiong; Yinan Song; Yu Zhou; Jianfu Zhang; Fong Sang Lam; Chao Xie; Wenyin Shen; Yiran Huang; Ling Meng; Xiaoyu Li
Angew. Chem. Int. Ed. Engl., 2020, 59 (35), 14965-14972
https://doi.org/10.1002/anie.202005070

Abstract

Dynamic combinatorial library (DCL) is a powerful tool for ligand discovery in biomedical research; however, the development of DCL has been hampered by its low diversity. Recently, the concept of DNA encoding has been employed in DCL to create DNA-encoded dynamic libraries (DEDLs); however, all current DEDLs are limited to fragment identification, and a challenging process of fragment linking is required after selection. We report an anchor-directed DEDL approach that can identify full ligand structures from large-scale DEDLs. This method is also able to convert unbiased libraries to focused ones targeting specific protein classes. We demonstrated this method by selecting DEDLs against five proteins, and novel inhibitors have been identified for all targets. Notably, several selective BD1/BD2 inhibitors were identified from the selections against BRD4 (bromodomain 4), an important anti-cancer drug target. This work may provide a broadly applicable method for inhibitor discovery.