Mittwoch, 24. Januar 2018, 16:15 - 17:30 iCal

Winter Georg, PhD

CeMM- Research Center for Molecular Medicine of the Austrian Academy of Sciences, Wien


„Chemical degradation of gene regulatory proteins”

Kleiner Hörsaal 3 der Fakultät für Chemie
Währinger Straße 38, 1090 Wien


Chemical degradation of gene regulatory proteins


Aberrant gene regulation underpins and sustains most if not all aspects of human malignancies. However, therapeutic targeting of oncogenic transcriptional circuits has posed a historic challenge in the field of ligand discovery chemistry ow-ing to the lack of druggable, enzymatically active domains in transcription factors and transcriptional co-activators. To overcome this limitation, and to expand the space of proteins amenable to therapeutic targeting, we recently devised a strategy for ligand-induced target protein degradation using bifunctional small molecules capable of chemically repro-gramming the E3 ligase substrate receptor cereblon (CRBN). In detail, these small molecules induce molecular proximity between CRBN and a protein of interest (POI). Induced proximity leads to ubiquitination of the POI and subsequent degra-dation by the proteasome. Focusing our initial efforts on degraders of the BET family of proteins, we could show that these agents induce pronounced target degradation in vitro as well as in vivo, thus outlining a potential avenue for further thera-peutic development. Moreover, we observed that they exhibit superior efficacy than competitive BET bromodomain inhibi-tors through largely unknown mechanisms. I will discuss our efforts to mechanistically explain this differential molecular pharmacology, as well as our efforts to extend this type of chemistry to new targets.



Fakultät für Chemie, Institut für Organische Chemie


Brigitte Schwarz
Fakultät für Chemie der Universität Wien