Disruption of Myc-Max heterodimerization with improved cell-penetrating analogs of the small molecule 10074-G5.
Disruption of Myc-Max heterodimerization with improved cell-penetrating analogs of the small molecule 10074-G5.
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DOI：
10.18632/oncotarget.1108
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Prochownik EV
中科院分区：
文献类型：
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作者：
Wang H;Chauhan J;Hu A;Pendleton K;Yap JL;Sabato PE;Jones JW;Perri M;Yu J;Cione E;Kane MA;Fletcher S;Prochownik EV
c-Myc (Myc) 癌蛋白是一个高价值的治疗靶点，因为它在多种类型的癌症中不受管制。然而，Myc 的有效小分子抑制剂一直难以识别，特别是那些其机制依赖于阻断 Myc 与其专性异二聚化伙伴 Max 之间的关联的抑制剂。我们最近报道了对此类小分子 10074-G5 的结构-活性关系研究，并生成了类似物 JY-3-094，其阻止或破坏重组 Myc 和 Max 蛋白之间关联的能力显着提高。然而，JY-3094 穿透细胞的能力较差。在这里，我们表明，JY-3-094 的关键对位羧酸功能通过各种封闭基团的酯化显着提高了细胞摄取，尽管它削弱了体外破坏 Myc-Max 缔合的能力。这些前药高度浓缩在细胞内，然后通过酯酶的作用生成 JY-3-094。然而，前药对细胞外酯酶的敏感性也不同，这会耗尽细胞外的储存库。此外，虽然 JY-3-094 被细胞保留很长时间，但其中大部分以似乎不太可能与 Myc 相互作用的形式划分在细胞质内。我们的结果表明，持续高的细胞外前药水平，且对细胞外酯酶不过度敏感，对于建立和维持足以长期抑制 Myc-Max 关联的 JY-3-094 细胞内水平至关重要。 JY-3-094 的类似物似乎代表了有前景的小分子 Myc 抑制剂，值得进一步优化。
The c-Myc (Myc) oncoprotein is a high-value therapeutic target given that it is deregulated in multiple types of cancer. However, potent small molecule inhibitors of Myc have been difficult to identify, particularly those whose mechanism relies on blocking the association between Myc and its obligate heterodimerization partner, Max. We have recently reported a structure-activity relationship study of one such small molecule, 10074-G5, and generated an analog, JY-3-094, with significantly improved ability to prevent or disrupt the association between recombinant Myc and Max proteins. However, JY-3094 penetrates cells poorly. Here, we show that esterification of a critical para-carboxylic acid function of JY-3-094 by various blocking groups significantly improves cellular uptake although it impairs the ability to disrupt Myc-Max association in vitro. These pro-drugs are highly concentrated within cells where JY-3-094 is then generated by the action of esterases. However, the pro-drugs are also variably susceptible to extracellular esterases, which can deplete extracellular reservoirs. Furthermore, while JY-3-094 is retained by cells for long periods of time, much of it is compartmentalized within the cytoplasm in a form that appears to be less available to interact with Myc. Our results suggest that persistently high extracellular levels of pro-drug, without excessive susceptibility to extracellular esterases, are critical to establishing and maintaining intracellular levels of JY-3-094 that are sufficient to provide for long-term inhibition of Myc-Max association. Analogs of JY-3-094 appear to represent promising small molecule Myc inhibitors that warrant further optimization.