Design, Construction, and Screening of Diversified Pyrimidine-Focused DNA-Encoded Libraries

Pyrimidineis a ubiquitous component in natural products and approveddrugs, providing an ideal modular scaffold for generating librarieswith drug-like properties. DNA-encoded library technology introducesa novel library modality where each small molecule is covalently linkedto a unique oligo tag. This technology offers the advantages of rapidlygenerating and interrogating large-scale libraries containing billionsof members, substantially reducing the entry barrier to their usein both academia and the pharmaceutical industry. In this Letter,we describe the synthesis of three DNA-encoded libraries based ondifferent functionalized pyrimidine cores featuring diversified chemoselectivityand regioselectivity. Preliminary screening of these DNA-encoded librariesagainst BRD4 identified compounds with nanomolar inhibition activities.