Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription
The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Elsevier BV
2020
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| Online Access: | https://hdl.handle.net/1721.1/125846 |
| _version_ | 1811001867643125760 |
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| author | Struntz, Nicholas B. Chen, Andrew I Deutzmann, Anja Wilson, Robert M. Stefan, Eric Evans, Helen L Ramirez, Maricela A. Liang, Tong Caballero, Francisco Wildschut, Mattheus H.E. Neel, Dylan V Freeman, David B. Pop, Marius S McConkey, Marie Muller, Sandrine Curtin, Brice Harrison Tseng, Hanna Frombach, Kristen R. Butty, Vincent L G Levine, Stuart S. Feau, Clementine Elmiligy, Sarah Hong, Jiyoung A. Lewis, Timothy A. Vetere, Amedeo Clemons, Paul A. Malstrom, Scott E. Ebert, Benjamin L. Lin, Charles Y. Felsher, Dean W. Koehler, Angela Nicole |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Struntz, Nicholas B. Chen, Andrew I Deutzmann, Anja Wilson, Robert M. Stefan, Eric Evans, Helen L Ramirez, Maricela A. Liang, Tong Caballero, Francisco Wildschut, Mattheus H.E. Neel, Dylan V Freeman, David B. Pop, Marius S McConkey, Marie Muller, Sandrine Curtin, Brice Harrison Tseng, Hanna Frombach, Kristen R. Butty, Vincent L G Levine, Stuart S. Feau, Clementine Elmiligy, Sarah Hong, Jiyoung A. Lewis, Timothy A. Vetere, Amedeo Clemons, Paul A. Malstrom, Scott E. Ebert, Benjamin L. Lin, Charles Y. Felsher, Dean W. Koehler, Angela Nicole |
| author_sort | Struntz, Nicholas B. |
| collection | MIT |
| description | The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc. |
| first_indexed | 2024-09-23T15:39:28Z |
| format | Article |
| id | mit-1721.1/125846 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:39:28Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1258462022-10-02T03:12:26Z Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription Struntz, Nicholas B. Chen, Andrew I Deutzmann, Anja Wilson, Robert M. Stefan, Eric Evans, Helen L Ramirez, Maricela A. Liang, Tong Caballero, Francisco Wildschut, Mattheus H.E. Neel, Dylan V Freeman, David B. Pop, Marius S McConkey, Marie Muller, Sandrine Curtin, Brice Harrison Tseng, Hanna Frombach, Kristen R. Butty, Vincent L G Levine, Stuart S. Feau, Clementine Elmiligy, Sarah Hong, Jiyoung A. Lewis, Timothy A. Vetere, Amedeo Clemons, Paul A. Malstrom, Scott E. Ebert, Benjamin L. Lin, Charles Y. Felsher, Dean W. Koehler, Angela Nicole Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc. National Cancer Institute (Grant R01-CA160860) National Cancer Institute (Grant P30-CA14051) National Cancer Institute (Grant U01-CA176152) National Cancer Institute (Grant CA170378PQ2) National Institutes of Health (Grant CA170378PQ2) 2020-06-17T18:32:55Z 2020-06-17T18:32:55Z 2019-05 Article http://purl.org/eprint/type/JournalArticle 2451-9456 https://hdl.handle.net/1721.1/125846 Struntz, Nicholas B. et al. "Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription." Cell Chemical Biology 26, 5 (May 2019): P711-723.e14 http://dx.doi.org/10.1016/j.chembiol.2019.02.009 Cell Chemical Biology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/zip application/pdf application/pdf Elsevier BV Andrew Chen |
| spellingShingle | Struntz, Nicholas B. Chen, Andrew I Deutzmann, Anja Wilson, Robert M. Stefan, Eric Evans, Helen L Ramirez, Maricela A. Liang, Tong Caballero, Francisco Wildschut, Mattheus H.E. Neel, Dylan V Freeman, David B. Pop, Marius S McConkey, Marie Muller, Sandrine Curtin, Brice Harrison Tseng, Hanna Frombach, Kristen R. Butty, Vincent L G Levine, Stuart S. Feau, Clementine Elmiligy, Sarah Hong, Jiyoung A. Lewis, Timothy A. Vetere, Amedeo Clemons, Paul A. Malstrom, Scott E. Ebert, Benjamin L. Lin, Charles Y. Felsher, Dean W. Koehler, Angela Nicole Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription |
| title | Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription |
| title_full | Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription |
| title_fullStr | Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription |
| title_full_unstemmed | Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription |
| title_short | Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription |
| title_sort | stabilization of the max homodimer with a small molecule attenuates myc driven transcription |
| url | https://hdl.handle.net/1721.1/125846 |
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