Synthetic molecules for disruption of the MYC protein-protein interface.
Synthetic molecules for disruption of the MYC protein-protein interface.
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DOI：
10.1016/j.bmc.2018.07.019
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发表时间：
2018-08-07
影响因子：
3.5
通讯作者：
Janda KD
中科院分区：
文献类型：
--
作者：
Jacob NT;Miranda PO;Shirey RJ;Gautam R;Zhou B;de Orbe Izquierdo ME;Hixon MS;Hart JR;Ueno L;Vogt PK;Janda KD
MYC是参与细胞增殖的关键转录调节因子，并在转录延伸和起始、microRNA调节、细胞凋亡和多能性中发挥作用。尽管如此，功能性化学探针在蛋白水平上的MYC功能仍然有限。在此之前，我们发现了5a，它与MYC结合的效力和特异性，下调MYC的转录活性，并在体内显示出疗效。然而，这种支架具有内在的药代动力学缺陷，即溶解度差，无法进行生物物理检查。在这里，我们开发了一个基于场效应晶体管分析（Bio-FET）、表面等离子体共振（SPR）和微肿瘤形成分析的筛选平台，以分析一系列旨在改善这些特性的新化合物。这种盲SAR运动产生了一种新的先导化合物，其体内稳定性和溶解度显著提高，暴露量增加了40倍。该探针代表了一项重大进展，不仅可以实现这种相互作用的生物物理表征和进一步的SAR，而且还有助于对MYC生物学的理解。
MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo. However, this scaffold posed intrinsic pharmacokinetic liabilities, namely, poor solubility that precluded biophysical interrogation. Here, we developed a screening platform based on field-effect transistor analysis (Bio-FET), surface plasmon resonance (SPR), and a microtumor formation assay to analyze a series of new compounds aimed at improving these properties. This blind SAR campaign has produced a new lead compound of significantly increased in vivo stability and solubility for a 40-fold increase in exposure. This probe represents a significant advancement that will not only enable biophysical characterization of this interaction and further SAR, but also contribute to advances in understanding of MYC biology.
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影响因子：
8.4
作者：
Lerner, Mitchell B.;Pan, Deng;Goldsmith, Brett R.
通讯作者：
Goldsmith, Brett R.
影响因子：
2.9
作者：
Hu, JZ;Banerjee, A;Goss, DJ
通讯作者：
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影响因子：
5.4
作者：
Conacci-Sorrell, Maralice;McFerrin, Lisa;Eisenman, Robert N.
通讯作者：
Eisenman, Robert N.
DOI：
10.1073/pnas.1319488111
发表时间：
2014-08-26
影响因子：
11.1
作者：
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通讯作者：
Janda, Kim D.
影响因子：
11.2
作者：
Ruggero D
通讯作者：
Ruggero D