Fragment-Based Discovery of AF9 YEATS Domain Inhibitors.
Fragment-Based Discovery of AF9 YEATS Domain Inhibitors.
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基于片段的 AF9 YEATS 结构域抑制剂的发现
DOI：
10.3390/ijms23073893
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发表时间：
2022-03-31
影响因子：
5.6
通讯作者：
Ruan K
中科院分区：
文献类型：
--
作者：
Liu Y;Jin R;Lu H;Bian K;Wang R;Wang L;Gao R;Zhang J;Wu J;Yao X;Liu X;Liu D;Wang X;Zhang Z;Ruan K
YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers.
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通过靶向 pi-pi-pi 堆积来结构引导开发 YEATS 结构域抑制剂。
影响因子：
14.8
作者：
Li X;Li XM;Jiang Y;Liu Z;Cui Y;Fung KY;van der Beelen SHE;Tian G;Wan L;Shi X;Allis CD;Li H;Li Y;Li XD
通讯作者：
Li XD
影响因子：
64.8
作者：
Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
通讯作者：
Bradner JE
基于自动 NMR 片段的筛选鉴定出 LARG/RhoA 复合物的新型界面阻断剂
影响因子：
3.7
作者：
Gao J;Ma R;Wang W;Wang N;Sasaki R;Snyderman D;Wu J;Ruan K
通讯作者：
Ruan K
DOI：
10.3390/molecules25173949
发表时间：
2020-08-29
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Johnson JA;Olson NM;Tooker MJ;Bur SK;Pomerantz WCK
通讯作者：
Pomerantz WCK
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K