ao8b00959_si_001.pdf (5.66 MB)
Chemical Ligand Space of Cereblon
journal contribution
posted on 2018-09-14, 13:39 authored by Iuliia Boichenko, Kerstin Bär, Silvia Deiss, Christopher Heim, Reinhard Albrecht, Andrei N. Lupas, Birte Hernandez Alvarez, Marcus D. HartmannThe protein cereblon
serves as a substrate receptor of a ubiquitin
ligase complex that can be tuned toward different target proteins
by cereblon-binding agents. This approach to targeted protein degradation
is exploited in different clinical settings and has sparked the development
of a growing number of thalidomide derivatives. Here, we probe the
chemical space of cereblon binding beyond such derivatives and work
out a simple set of chemical requirements, delineating the metaclass
of cereblon effectors. We report co-crystal structures for a diverse
set of compounds, including commonly used pharmaceuticals, but also
find that already minimalistic cereblon-binding moieties might exert
teratogenic effects in zebrafish. Our results may guide the design
of a post-thalidomide generation of therapeutic cereblon effectors
and provide a framework for the circumvention of unintended cereblon
binding by negative design for future pharmaceuticals.