Open AccessDiscovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain
Author(s) -
R. Xinyu,
Liguang Xu,
Shiqing Xu,
Brianna J. Klein,
Hongkuan Wang,
Saibal Das,
Kuai Li,
Kun Yang,
S. Qazi Sohail,
Andrew Chapman,
Tatiana G. Kutateladze,
Xiaobing Shi,
Wenshe Ray Liu,
Hong Wen
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00367
Subject(s) - bromodomain , chemistry , small molecule , acetylation , leukemia , histone , phenotypic screening , structure–activity relationship , lysine , high throughput screening , biochemistry , computational biology , cancer research , microbiology and biotechnology , in vitro , gene , phenotype , genetics , biology , amino acid
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 IC 50 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.