Shaozhao Qin; Lijian Feng; Qingyi Zhao; Ziqin Yan; Xilin Lyu; Kaige Li; Baiyang Mu; Yujie Chen; Weiwei Lu; Chao Wang; Yanrui Suo; Jinfeng Yue; Mengqing Cui; Yingjie Li; Yujun Zhao; Zhiqiang Duan; Jidong Zhu; Xiaojie Lu
J. Med. Chem., 2024, 67(2), 1079–1092
https://doi.org/10.1021/acs.jmedchem.3c01463

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.