| Literature DB >> 34279931 |
Xinyu R Ma1, Longxia Xu2, Shiqing Xu1, Brianna J Klein3, Hongkuan Wang2, Sukant Das1, Kuai Li2, Kai S Yang1, Sana Sohail2, Andrew Chapman1, Tatiana G Kutateladze3, Xiaobing Shi2, Wenshe Ray Liu1,4,5,6, Hong Wen2.
Abstract
Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.Entities:
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Year: 2021 PMID： 34279931 PMCID： PMC8486320 DOI： 10.1021/acs.jmedchem.1c00367
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039