| Literature DB >> 28930682 |
Nina Kerres1, Steffen Steurer1, Stefanie Schlager1, Gerd Bader1, Helmut Berger1, Maureen Caligiuri2, Christian Dank1, John R Engen3, Peter Ettmayer1, Bernhard Fischerauer1, Gerlinde Flotzinger1, Daniel Gerlach1, Thomas Gerstberger1, Teresa Gmaschitz1, Peter Greb1, Bingsong Han2, Elizabeth Heyes1, Roxana E Iacob3, Dirk Kessler1, Heike Kölle4, Lyne Lamarre1, David R Lancia2, Simon Lucas1, Moriz Mayer1, Katharina Mayr1, Nikolai Mischerikow1, Katja Mück4, Christoph Peinsipp1, Oliver Petermann1, Ulrich Reiser1, Dorothea Rudolph1, Klaus Rumpel1, Carina Salomon1, Dirk Scharn1, Renate Schnitzer1, Andreas Schrenk1, Norbert Schweifer1, Diane Thompson1, Elisabeth Traxler1, Roland Varecka1, Tilman Voss1, Alexander Weiss-Puxbaum1, Sandra Winkler1, Xiaozhang Zheng2, Andreas Zoephel1, Norbert Kraut1, Darryl McConnell1, Mark Pearson1, Manfred Koegl5.
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.Entities:
Keywords: BTB domain; cancer; drug discovery; drug target; lymphoma; oncogene; transcription factor; ubiquitin
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Year: 2017 PMID： 28930682 DOI： 10.1016/j.celrep.2017.08.081
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423