Ebert Laboratory, Harvard Medical School, Boston, Massachusetts, USA
Gluing the pieces together: Illuminating the path to degrading troublesome
Molecular glue degraders hold great therapeutic promise, yet because their discoveries
have been serendipitous, their design principles remain unclear. We developed new
approaches to systematically identify such degraders and discovered a diverse class
of compounds that deplete cyclin K. To investigate how chemically dissimilar small
molecules can all trigger cyclin K degradation, we evaluated 91 putative degraders in
structural, biophysical, and cellular assays.
We discovered that they function by simultaneously binding to CDK12-cyclin K and the
ubiquitin ligase adaptor DDB1 and solved 29 crystal structures of compound-induced
complexes. This systematic study of the relationships between the glue’s structure and
activity provides a framework for designing and optimizing molecular glue degraders.
We further demonstrate cyclin K degraders have distinct transcriptional signatures,
thereby offering unique therapeutic opportunities.
Zuzanna grew up in Kraków, Poland. She moved to the UK for an undergraduate degree
in Medicinal and Biological Chemistry at the University of Edinburgh. Inspired by a year-
long internship with Prof. Nenad Ban at the ETH Zürich and a summer project with Prof.
Alessio Ciulli in Dundee during her studies, Zuzanna relocated to Switzerland to pursue
a PhD with Dr. Nicolas Thomä with a focus on targeted protein degradation. She worked
on molecular glue degraders, which are compounds able to inactivate disease-causing
proteins through sending them to the cellular waste disposal system. Her research
identified a novel class of glues and yielded insights into how such drugs could be designed.
Zuzanna recently began her postdoctoral work at the Dana Farber Cancer Institute and
MIT with Prof. Benjamin Ebert and Prof. Angela Koehler, continuing to explore how
compounds can bring together seemingly unrelated proteins.