Abstract 1525: Chemically induced degradation of the oncogenic transcription factor BCL6

Abstract

Abstract The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). It is a DNA-binding protein that represses gene transcription through the recruitment of co-repressor proteins via its BTB domain. Disruption of the interaction of BCL6 with co-repressor proteins interferes with the physiological and oncogenic functions of BCL6. We have used structure-based drug desgin to develop potent compounds that block this interaction with half maximal inhibitory concentration values (IC50s) below 3 nM. In addition to inhibiting co-repressor binding, a subset of the identified inhibitors also caused rapid disappearance of BCL6 protein in cells. This effect was mediated by compound-induced multi-ubiquitylation of BCL6 and degradation by the proteasome and was dependent on the presence of a functional DNA binding domain on BCL6. Compounds that induced BCL6 degradation displayed significantly stronger induction of expression of BCL6-repressed genes than compounds that merely inhibited co-repressor interaction. BCL6-degrading inhibitors had anti-proliferative effects in several DLBCL cell lines, while non-degrading BCL6 inhibitors only had minor effects on proliferation. The fact that the magnitude of effects elicited by this novel class of BCL6 degrading compounds greatly exceeds that of our equipotent classical co-repressor interaction inhibitors offers exciting new opportunities for the development of BCL6-based lymphoma therapeutics. Citation Format: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Sophia Blake, Maureen Caligiuri, John Engen, Peter Ettmayer, Thomas Gerstberger, Daniel Gerlach, Roxana Jacob, Simon Lucas, Moriz Mayer, Mischerikow Nikolai, Rumpel Klaus, Scharn Dirk, Schnitzer Renate, Tilman Voss, Zoephel Andreas, Norbert Kraut, Darryl McConnell, Pearson Mark, Manfred Koegl. Chemically induced degradation of the oncogenic transcription factor BCL6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1525. doi:10.1158/1538-7445.AM2017-1525