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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