Inhibitor of MYC identified in a Krohnke pyridine library
Inhibitor of MYC identified in a Krohnke pyridine library
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DOI：
10.1073/pnas.1319488111
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发表时间：
2014-08-26
影响因子：
11.1
通讯作者：
Janda, Kim D.
中科院分区：
文献类型：
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作者：
Hart, Jonathan R.;Garner, Amanda L.;Janda, Kim D.
在MYC-MAX相互作用的荧光偏振筛选中，我们从Krohnke吡啶库中鉴定出一种新型MYC小分子抑制剂KJ-Pyr-9。KJ-Pyr-9在体外对MYC的Kd为6.5 +/- 1.0 nM，通过反向散射干涉法测定; KJ-Pyr-9还干扰细胞中MYC-MAX复合物的形成，如蛋白片段互补测定所示。KJ-Pyr-9特异性抑制细胞培养中MYC诱导的致癌转化;它对几种不相关癌蛋白的致癌活性没有或只有微弱的影响。KJ-Pyr-9优先干扰MYC过表达的人类和禽类细胞的增殖，并特异性地减少MYC驱动的转录特征。在体内，KJ-Pyr-9有效地阻断MYC扩增的人类癌细胞的异种移植物的生长。
In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Krohnke pyridine library. The K-d of KJ-Pyr-9 for MYC in vitro is 6.5 +/- 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.