Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.
Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.
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DOI：
10.1158/0008-5472.can-20-3108
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发表时间：
2021-04-01
期刊：
影响因子：
11.2
通讯作者：
Mossé YP
中科院分区：
文献类型：
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作者：
Wolpaw AJ;Bayliss R;Büchel G;Dang CV;Eilers M;Gustafson WC;Hansen GH;Jura N;Knapp S;Lemmon MA;Levens D;Maris JM;Marmorstein R;Metallo SJ;Park JR;Penn LZ;Rape M;Roussel MF;Shokat KM;Tansey WP;Verba KA;Vos SM;Weiss WA;Wolf E;Mossé YP
儿科实体瘤的有效治疗受到目前“不可药物化”的驱动转录因子的优势的阻碍。改善结果，同时降低治疗的毒性需要开发新的药物，可以直接抑制或降解这些难以捉摸的目标。小儿神经源性肿瘤（包括神经母细胞瘤和髓母细胞瘤）中的MYCN是这个问题的典型例子。直接和特异性靶向MYCN的尝试已经失败，这是由于其与MYC的相似性、MYC家族蛋白以其单体形式的非结构化性质、缺乏对MYCN相互作用蛋白的理解和在体内测试其相关性的能力、无法获得关于MYCN蛋白复合物的结构信息以及使用传统小分子抑制蛋白质-蛋白质或蛋白质-DNA相互作用的挑战。然而，现在有希望根据所有这些方面的科学和技术进步，直接针对MYCN。在这里，我们讨论了先前的挑战和重新乐观的原因，直接靶向这种“不可药”的转录因子，我们希望这将导致改善儿童癌症患者的结果，并创建一个框架，靶向驱动癌蛋白调节基因转录。
Effective treatment of pediatric solid tumors has been hampered by the predominance of currently ‘undruggable’ driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein-protein or protein-DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here we discuss prior challenges and the reasons for renewed optimism in directly targeting this ‘undruggable’ transcription factor, which we hope will lead to improved outcomes for pediatric cancer patients and create a framework for targeting driver oncoproteins regulating gene transcription.