Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.
Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.
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DOI：
10.1021/acscentsci.0c01550
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发表时间：
2021-05-26
影响因子：
18.2
通讯作者：
Erb MA
中科院分区：
文献类型：
--
作者：
Garnar-Wortzel L;Bishop TR;Kitamura S;Milosevich N;Asiaban JN;Zhang X;Zheng Q;Chen E;Ramos AR;Ackerman CJ;Hampton EN;Chatterjee AK;Young TS;Hull MV;Sharpless KB;Cravatt BF;Wolan DW;Erb MA
转录共调节因子介导染色质依赖的转录信号，是用小分子调节致癌基因表达程序的容易处理的靶点。最近的遗传功能丧失研究表明，转录辅助激活因子ENL是急性白血病生存的选择性要求，并强调了其染色质阅读器Yeats结构域的重要作用。在这些发现的推动下，我们对近300,000个小分子进行了筛选，并确定了enl Yeats结构域的氨基咪唑并吡啶抑制剂(IC_(50)=7μM)。通过采用和扩展基于SuFEx的高通量药物化学方法，最终证明它与基于细胞的药物发现兼容，从而改进了最初的筛选成功。通过这些努力，我们发现了一种有效和选择性的ENL/AF9 Yeats结构域抑制剂SR-0813(IC50=25 nM)。有了这个工具和一流的ENL PROTAC，SR-1114，我们第一次详细描述了AML细胞对药理学ENL破坏的生物学反应。最值得注意的是，我们发现enl Yeats抑制足以选择性地抑制enl靶基因，包括HOXA9/10、myb、myc和一些其他白血病原癌基因。综上所述，我们的研究确立了抑制Yeats结构域是一种可行的方法来干扰ENL在急性白血病中的致病功能，并为ENL Yeats结构域提供了第一个全面表征的化学探针。通过高通量筛选确定了enl Yeats结构域的抑制物，通过PROTAC发现进行了验证，并通过高通量SuFEx多样化进行了优化。
Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50 = 7 μM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain. An inhibitor of the ENL YEATS domain, an emerging leukemia target, was identified by high-throughput screening, validated by PROTAC discovery, and optimized by high-throughput SuFEx diversification.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
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
影响因子：
8.6
作者：
Brand, Matthias;Jiang, Baishan;Winter, Georg E.
通讯作者：
Winter, Georg E.