Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
- 28 January 2021
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (7), 1627-1632
- https://doi.org/10.1158/0008-5472.can-20-3108
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 pediatric cancer patients and create a framework for targeting driver oncoproteins that regulate gene transcription.Funding Information
- Alex's Lemonade Stand Foundation for Childhood Cancer (Crazy 8 Targeting MYCN Pilot)
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