Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription
Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription
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DOI：
10.1016/j.chembiol.2019.02.009
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发表时间：
2019-05-16
影响因子：
8.6
通讯作者：
Koehler, Angela N.
中科院分区：
文献类型：
--
作者：
Struntz, Nicholas B.;Chen, Andrew;Koehler, Angela N.
转录因子 Max 是一种碱性螺旋环螺旋亮氨酸拉链 (bHLHLZ) 蛋白，可形成同二聚体或与其他 bHLHLZ 蛋白（包括 Myc 和 Mxd 蛋白）相互作用。在这个相互作用的动态网络中，Myc/Max 异二聚体在调节正常细胞过程中发挥着至关重要的作用，但其转录活性在大多数人类癌症中不受调节。尽管具有重要意义，但用于研究这些蛋白质的高质量化学探针仍然有限。我们使用小分子微阵列来识别以机械公正的方式结合 Max 的化合物。我们发现了不对称多环内酰胺 KI-MS2-008，它可以稳定 Max 同二聚体，同时降低 Myc 蛋白和 Myc 调节的转录物水平。 KI-MS2-008 还以 Myc 依赖性方式减少活癌细胞生长，并抑制体内肿瘤生长。该方法证明了用小分子调节 Max 的可行性，并支持改变 Max 二聚化作为靶向 Myc 的替代方法。
The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.