1. Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
- Author
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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, and Mossé, Yaël P
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Neuroblastoma ,Cancer ,Rare Diseases ,Genetics ,Neurosciences ,Pediatric Cancer ,Pediatric ,5.1 Pharmaceuticals ,Age of Onset ,Antineoplastic Agents ,Child ,Drug Discovery ,Drug Resistance ,Neoplasm ,Drug Screening Assays ,Antitumor ,Gene Expression Regulation ,Neoplastic ,History ,20th Century ,History ,21st Century ,Humans ,N-Myc Proto-Oncogene Protein ,Neoplasms ,Therapies ,Investigational ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - 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.
- Published
- 2021