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.
- 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].
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.