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. 2017 Sep 19;20(12):2860-2875.
doi: 10.1016/j.celrep.2017.08.081.

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Nina Kerres  1 , Steffen Steurer  1 , Stefanie Schlager  1 , Gerd Bader  1 , Helmut Berger  1 , Maureen Caligiuri  2 , Christian Dank  1 , John R Engen  3 , Peter Ettmayer  1 , Bernhard Fischerauer  1 , Gerlinde Flotzinger  1 , Daniel Gerlach  1 , Thomas Gerstberger  1 , Teresa Gmaschitz  1 , Peter Greb  1 , Bingsong Han  2 , Elizabeth Heyes  1 , Roxana E Iacob  3 , Dirk Kessler  1 , Heike Kölle  4 , Lyne Lamarre  1 , David R Lancia  2 , Simon Lucas  1 , Moriz Mayer  1 , Katharina Mayr  1 , Nikolai Mischerikow  1 , Katja Mück  4 , Christoph Peinsipp  1 , Oliver Petermann  1 , Ulrich Reiser  1 , Dorothea Rudolph  1 , Klaus Rumpel  1 , Carina Salomon  1 , Dirk Scharn  1 , Renate Schnitzer  1 , Andreas Schrenk  1 , Norbert Schweifer  1 , Diane Thompson  1 , Elisabeth Traxler  1 , Roland Varecka  1 , Tilman Voss  1 , Alexander Weiss-Puxbaum  1 , Sandra Winkler  1 , Xiaozhang Zheng  2 , Andreas Zoephel  1 , Norbert Kraut  1 , Darryl McConnell  1 , Mark Pearson  1 , Manfred Koegl  5
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Free article

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Nina Kerres et al. Cell Rep. .
Free article

Abstract

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.

Keywords: BTB domain; cancer; drug discovery; drug target; lymphoma; oncogene; transcription factor; ubiquitin.

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