Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
Name
Wolpaw_MYCN_2020_11_20_revisedjmm_ypmww.pdf
Description
Accepted version
Size
379.55 KB
Format
Adobe PDF
Checksum (MD5)
2cd1b896d71dc674134dd3007ef1ae94
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.
Date Issued
January 2021
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
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1158/0008-5472.can-20-3108
