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

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.