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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Glavni autori: 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.
Daljnji autori: Massachusetts Institute of Technology. Department of Biology
Format: Članak
Jezik:English
Izdano: American Association for Cancer Research (AACR) 2021
Online pristup:https://hdl.handle.net/1721.1/131155
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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.
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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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