Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach

Abstract

The DNA-encoded library (DEL) is a powerful hit generation tool for chemical biology and drug discovery; however, the optimization of DEL hits remained a daunting challenge for the medicinal chemistry community. In this study, hit compounds targeting the WIN binding domain of WDR5 were discovered by the initial three-cycle linear DEL selection, and their potency was further enhanced by a cascade DEL selection from the focused DEL designed based on the original first run DEL hits. As expected, these new compounds from the second run of focused DEL were more potent WDR5 inhibitors in the protein binding assay confirmed by the off-DNA synthesis. Interestingly, selected inhibitors exhibited good antiproliferative activity in two human acute leukemia cell lines. Taken together, this new cascade DEL selection strategy may have tremendous potential for finding high-affinity leads against WDR5 and provide opportunities to explore and optimize inhibitors for other targets.

Discovery of Two Non-Udp-Mimic Inhibitors of O-Glcnac Transferase by Screening a Dna-Encoded Library

“…The technology uses the combinatorial synthesis method to build up large libraries [30]. Since 2002 the DEL technology is a tool in medicinal chemistry for screening purposes where identification of hits is facilitated by the DNA tag [31][32][33][34][35][36][37]. Here we report on the discovery of new non-UDP mimetic OGT inhibitors by using the DELopen platform, a DEL available to academic users by WuXi AppTec.…”