Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

  • Cell Rep. 2017 Sep 19;20(12):2860-2875. doi: 10.1016/j.celrep.2017.08.081.
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
Affiliations
  • 1. Boehringer Ingelheim RCV GmbH & Co KG, 1221 Vienna, Austria.
  • 2. FORMA Therapeutics, Watertown, MA 02472, USA.
  • 3. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • 4. Boehringer Ingelheim, MedChem, Structural Research, Birkendorfer Str. 65, 88397 Biberach, Germany.
  • 5. Boehringer Ingelheim RCV GmbH & Co KG, 1221 Vienna, Austria. Electronic address: [email protected].
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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