Chemical Ligand Space of Cereblon
Posted on 2018-09-14 - 13:39
The 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.
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Boichenko, Iuliia; Bär, Kerstin; Deiss, Silvia; Heim, Christopher; Albrecht, Reinhard; N. Lupas, Andrei; et al. (2018). Chemical Ligand Space of Cereblon. ACS Publications. Collection. https://doi.org/10.1021/acsomega.8b00959
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AUTHORS (8)
IB
Iuliia Boichenko
KB
Kerstin Bär
SD
Silvia Deiss
CH
Christopher Heim
RA
Reinhard Albrecht
AN
Andrei N. Lupas
BA
Birte Hernandez Alvarez
MD
Marcus D. Hartmann