Mengnisa Seydimemet; Yixuan Yang; Yuhan Lv; Jiaxiang Liu; Ziqin Yan; Yujun Zhao; Xuan Wang; Xiaojie Lu
ACS Med. Chem. Lett., 2023, 14(8), 1073-1078
https://doi.org/10.1021/acsmedchemlett.3c00205

Abstract

Pyrimidine is a ubiquitous component in natural products and approved drugs, providing an ideal modular scaffold for generating libraries with drug-like properties. DNA-encoded library technology introduces a novel library modality where each small molecule is covalently linked to a unique oligo tag. This technology offers the advantages of rapidly generating and interrogating large-scale libraries containing billions of members, substantially reducing the entry barrier to their use in both academia and the pharmaceutical industry. In this Letter, we describe the synthesis of three DNA-encoded libraries based on different functionalized pyrimidine cores featuring diversified chemoselectivity and regioselectivity. Preliminary screening of these DNA-encoded libraries against BRD4 identified compounds with nanomolar inhibition activities.