1. Academic Validation
  2. Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

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

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: manfred.koegl@boehringer-ingelheim.com.
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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