| Autor: |
David R. Lancia, John R. Engen, Elizabeth Heyes, Katharina Mayr, Lyne Lamarre, Mark Pearson, Carina Salomon, Simon Lucas, Steffen Steurer, Alexander Weiss-Puxbaum, Klaus Rumpel, Gerlinde Flotzinger, Norbert Kraut, Xiaozhang Zheng, Daniel Gerlach, Katja Mück, Sandra Winkler, Heike Kölle, Peter Ettmayer, Nikolai Mischerikow, Christian Dank, Ulrich Reiser, Dirk Scharn, Bingsong Han, Teresa Gmaschitz, Andreas Schrenk, Nina Kerres, Norbert Schweifer, Dirk Kessler, Tilman Voss, Renate Schnitzer, Manfred Koegl, Roland Varecka, Moriz Mayer, Dorothea Rudolph, Oliver Petermann, Diane Thompson, Thomas Gerstberger, Christoph Peinsipp, Roxana E. Iacob, Stefanie Schlager, Gerd Bader, Helmut Berger, Peter Greb, Maureen Caligiuri, Elisabeth Traxler, Bernhard Fischerauer, Andreas Zoephel, Darryl B. McConnell |
| Rok vydání: |
2017 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 20, Iss 12, Pp 2860-2875 (2017) |
| ISSN: |
2211-1247 |
| Popis: |
Summary The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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