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Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers

Author(s)
Wolpaw, Adam J.; Bayliss, Richard; Büchel, Gabriele; Dang, Chi V.; Eilers, Martin; Gustafson, W. Clay; Hansen, Gwenn H.; Jura, Natalia; Knapp, Stefan; Lemmon, Mark A.; Levens, David; Maris, John M.; Marmorstein, Ronen; Metallo, Steven J.; Park, Julie R.; Penn, Linda Z.; Rape, Michael; Roussel, Martine F.; Shokat, Kevan M.; Tansey, William P.; Verba, Kliment A.; Vos, Seychelle M.; Weiss, William A.; Wolf, Elmar; Mossé, Yaël P.; ... Show more Show less
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Abstract
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 patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.
Date issued
2021-01
URI
https://hdl.handle.net/1721.1/131155
Department
Massachusetts Institute of Technology. Department of Biology
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Wolpaw, Adam J. et al. "Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers." Cancer Research 81, 7 (January 2021): 1627-1632. © 2021 American Association for Cancer Research
Version: Author's final manuscript
ISSN
0008-5472
1538-7445

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