Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues

Cullin-RING Ligase 4 Cereblon (CRL4CRBN) (CRBN) E3 ligase modulatory drugs (CELMoDsTM) make up a successful class of compounds targeting neosubstrates
for proteasome-dependent degradation. Early immunomodulatory drugs
(IMiDsTM) target Ikaros and Aiolos degradation.
In addition, there are ongoing clinical trials targeting the degradation
of biologically relevant proteins such as GSPT1, CK1α, and Helios
with CRBN-based molecular glues. To date, most advanced preclinical
and clinical CRBN-based molecular glues recruit their neosubstrates
through canonical G-motifs, secondary protein features that are structurally
similar but have significantly different amino acid sequence identities.
Analogous to the development of kinase inhibitors, optimizing both
neosubstrate recruitment and degradation selectivity is important
to minimize potential off-target activity. Here, we describe a computational
structure-based approach to analyze and predict putative ligand interactions
important in the neosubstrate ternary complex. This approach provides
valuable insights for enhanced designs toward the development of more
selective and efficacious CRBN-based molecular glues.