Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC.
Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC.
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DOI：
10.1016/j.chembiol.2020.09.001
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发表时间：
2021-01-21
影响因子：
8.6
通讯作者：
Nomura DK
中科院分区：
文献类型：
--
作者：
Boike L;Cioffi AG;Majewski FC;Co J;Henning NJ;Jones MD;Liu G;McKenna JM;Tallarico JA;Schirle M;Nomura DK
MYC是大多数人类癌症的主要致癌转录驱动因子，其仍然难以直接靶向，因为许多MYC本质上是无序的。在这里，我们已经进行了半胱氨酸反应性共价配体筛选，以确定化合物，可以破坏MYC的结合，其DNA的共识序列在体外，也损害MYC的转录活性在原位细胞。我们已经确定了一个共价配体EN 4，其靶向MYC的半胱氨酸171（C171），该蛋白质的预测的内在无序区域内。我们发现EN 4直接靶向细胞中的MYC，降低MYC和MAX的热稳定性，抑制MYC转录活性，下调多个MYC转录靶点，并损害肿瘤发生。我们还显示了EN 4的初始结构-活性关系，并确定了显示出改善效力的化合物。总体而言，我们确定了一个独特的ligandable网站内的一个内在的无序区域的MYC，导致抑制MYC的转录活性。我们鉴定了一种共价配体，其在功能上靶向MYC内在无序区域内的新型可配位位点C171，以降低MYC和MAX热稳定性，抑制MYC DNA结合，抑制MYC转录活性，下调MYC转录靶点，并损害增殖和肿瘤发生。
MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand EN4 that targets cysteine 171 (C171) of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity. We identify a covalent ligand that functionally targets a novel ligandable site C171 within an intrinsically disordered region of MYC to reduce MYC and MAX thermal stability, inhibit MYC DNA binding, inhibit MYC transcriptional activity, downregulate MYC transcriptional targets, and impair proliferation and tumorigenesis.
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影响因子：
19
作者：
Wolf, Elmar;Lin, Charles Y.;Eilers, Martin;Levens, David L.
通讯作者：
Levens, David L.
影响因子：
4
作者：
Ward, Carl C.;Kleinman, Jordan I.;Nomura, Daniel K.
通讯作者：
Nomura, Daniel K.
影响因子：
8.6
作者：
Struntz, Nicholas B.;Chen, Andrew;Koehler, Angela N.
通讯作者：
Koehler, Angela N.
影响因子：
50.3
作者：
Han, Huiying;Jain, Atul D.;Abdulkadir, Sarki A.
通讯作者：
Abdulkadir, Sarki A.
DOI：
10.1038/nrc.2017.36
发表时间：
2017-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Dang CV;Reddy EP;Shokat KM;Soucek L
通讯作者：
Soucek L