Selection of DNA-Encoded Dynamic Chemical Libraries for Direct Inhibitor Discovery
Yuqing Deng1, Jianzhao Peng1,2, Feng Xiong1
1Department of Chemistry and the State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Laboratory for Synthetic Chemistry and Chemical Biology of Health@InnoHK of Innovation and Technology Commission, Pokfulam Road, Hong Kong SAR, China.
Abstract:
Dynamic combinatorial libraries (DCLs) is a powerful tool for ligand discovery in biomedical research; however, the application of DCLs has been hampered by their low diversity. Recently, the concept of DNA encoding has been employed in DCLs 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 into focused ones targeting specific protein classes. We demonstrated this method by selecting DEDLs against five proteins, and novel inhibitors were identified for all targets. Notably, several selective BD1/BD2 inhibitors were identified from the selections against bromodomain 4 (BRD4), an important anti-cancer drug target. This work may provide a broadly applicable method for inhibitor discovery.
