De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives

Targeted
protein degradation via cereblon (CRBN), a substrate receptor
of an E3 ubiquitin ligase complex, is an increasingly important strategy
in various clinical settings, in which the substrate specificity of
CRBN is altered via the binding of small-molecule effectors. To date,
such effectors are derived from thalidomide and confer a broad substrate
spectrum that is far from being fully characterized. Here, we employed
a rational and modular approach to design novel and minimalistic CRBN
effectors. In this approach, we took advantage of the binding modes
of hydrolyzed metabolites of several thalidomide-derived effectors,
which we elucidated via crystallography. These yielded key insights
for the optimization of the minimal core binding moiety and its linkage
to a chemical moiety that imparts substrate specificity. Based on
this scaffold, we present a first active de-novo CRBN effector that
is able to degrade the neo-substrate IKZF3 in the cell culture.