Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
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...
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| Format: | Article |
| Language: | English |
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American Association for Cancer Research (AACR)
2021
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| Online Access: | https://hdl.handle.net/1721.1/131155 |
| _version_ | 1826206260383449088 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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. |
| author_sort | Wolpaw, Adam J. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:26:37Z |
| format | Article |
| id | mit-1721.1/131155 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:26:37Z |
| publishDate | 2021 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1311552022-10-01T15:21:36Z Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers 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. Massachusetts Institute of Technology. Department of Biology 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. 2021-08-09T19:38:26Z 2021-08-09T19:38:26Z 2021-01 2020-12 2021-08-05T18:04:13Z Article http://purl.org/eprint/type/JournalArticle 0008-5472 1538-7445 https://hdl.handle.net/1721.1/131155 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 en http://dx.doi.org/10.1158/0008-5472.can-20-3108 Cancer Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) Prof. Seychelle Vos |
| spellingShingle | 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. Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers |
| title | Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers |
| title_full | Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers |
| title_fullStr | Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers |
| title_full_unstemmed | Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers |
| title_short | Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers |
| title_sort | drugging the undruggable mycn oncogenic transcription factor overcoming previous obstacles to impact childhood cancers |
| url | https://hdl.handle.net/1721.1/131155 |
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