Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Publication date: 19 September 2017
Source:Cell Reports, Volume 20, Issue 12
Author(s): Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Maureen Caligiuri, Christian Dank, John R. Engen, Peter Ettmayer, Bernhard Fischerauer, Gerlinde Flotzinger, Daniel Gerlach, Thomas Gerstberger, Teresa Gmaschitz, Peter Greb, Bingsong Han, Elizabeth Heyes, Roxana E. Iacob, Dirk Kessler, Heike Kölle, Lyne Lamarre, David R. Lancia, Simon Lucas, Moriz Mayer, Katharina Mayr, Nikolai Mischerikow, Katja Mück, Christoph Peinsipp, Oliver Petermann, Ulrich Reiser, Dorothea Rudolph, Klaus Rumpel, Carina Salomon, Dirk Scharn, Renate Schnitzer, Andreas Schrenk, Norbert Schweifer, Diane Thompson, Elisabeth Traxler, Roland Varecka, Tilman Voss, Alexander Weiss-Puxbaum, Sandra Winkler, Xiaozhang Zheng, Andreas Zoephel, Norbert Kraut, Darryl McConnell, Mark Pearson, Manfred Koegl
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.

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Teaser

Kerres et al. show that the BTB domain of BCL6 is highly druggable and that potent binders can be derived that cause rapid degradation of BCL6. Inhibitors that induce degradation cause stronger anti-proliferative effects than other BCL6 inhibitors and offer new routes to the development of lymphoma treatments.


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