Molecular
glues are small molecules that simultaneously bind to
two proteins, creating a chemically induced protein–protein
interface. CELMoDs (cereblon E3 ligase modulators) are a class of
molecular glues that promote recruitment of neosubstrate proteins
to the E3 ubiquitin ligase cereblon (CRBN) for poly-Lys48-ubiquitination
and proteasomal degradation. Ternary complex structures of clinical
CELMoDs CC-885 and CC-90009 bound to CRBN and neosubstrate G1 to S
phase transition protein 1 (GSPT1) have been experimentally determined.
Although cellular degradation is a downstream event, dependent not
only on the affinity of the glue CELMoD in the ternary complex, we
test the applicability of established structure-based drug design
principles to predict binding affinity of CELMoDs to the protein–protein
neointerface and correlation to measured cellular degradation for
the neosubstrates GSPT1 and zinc finger Aiolos (IKZF3). For a congeneric
series of CELMoDs, which have a similar sequence of binding events
and resultant binding modes, we conclude that well-established structure-based
methods that measure in silico ternary complex stabilities can predict
relative degradation potency by CELMoDs.
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