Cell Reports (Sep 2017)

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

  • 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

DOI
https://doi.org/10.1016/j.celrep.2017.08.081
Journal volume & issue
Vol. 20, no. 12
pp. 2860 – 2875

Abstract

Read online

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