Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

Immunomodulatory
imide drugs (IMiDs) such as thalidomide, pomalidomide,
and lenalidomide are the most common cereblon (CRBN) recruiters in
proteolysis-targeting chimera (PROTAC) design. However, these CRBN
ligands induce the degradation of IMiD neosubstrates and are inherently
unstable, degrading hydrolytically under moderate conditions. In this
work, we simultaneously optimized physiochemical properties, stability,
on-target affinity, and off-target neosubstrate modulation features
to develop novel nonphthalimide CRBN binders. These efforts led to
the discovery of conformationally locked benzamide-type derivatives
that replicate the interactions of the natural CRBN degron, exhibit
enhanced chemical stability, and display a favorable selectivity profile
in terms of neosubstrate recruitment. The utility of the most potent
ligands was demonstrated by their transformation into potent degraders
of BRD4 and HDAC6 that outperform previously described reference PROTACs.
Together with their significantly decreased neomorphic ligase activity
on IKZF1/3 and SALL4, these ligands provide opportunities for the
design of highly selective and potent chemically inert proximity-inducing
compounds.