A screen identified 15 C2H2 zinc finger degrons that are degraded by thalidomide analogues.
Major finding: A screen identified 15 C2H2 zinc finger degrons that are degraded by thalidomide analogues.
Mechanism: Crystal structures revealed how zinc finger degrons bind to the drug–CRBN interface.
Impact: Chemical modification of thalidomide analogues may enable selective targeting of C2H2 ZF transcription factors.
Thalidomide and its derivatives are approved for the treatment of hematologic malignancies including multiple myeloma, del(5q) myelodysplastic syndrome, and mantle cell lymphoma. Thalidomide binds to CRBN, the substrate receptor of the CUL4–RBX1–DDB1–CRBN (CRL4CRBN) E3 ubiquitin ligase, and promotes recruitment of the C2H2 zinc finger (ZF) domain–containing transcription factors IKZF1 and IKZF3, leading to ubiquitination and proteasomal degradation of IKZF1 and IKZF3. Sievers, Petzold, and colleagues sought to characterize the ZF “degrome,” proteins degraded in the presence of CRL4CRBN and thalidomide analogues, and determine if modifications could alter the ZF selectivity of thalidomide compounds to potentially target different transcription factors. Screening a library of 6,572 C2H2 zinc fingers for degradation in the presence of thalidomide, lenalidomide, and pomalidomide revealed 11 ZF motifs capable of mediating drug-dependent degradation, termed degrons. These 11 degrons did not share a consensus sequence, and 6 promoted degradation of their full-length protein. The crystal structures of CRBN bound to pomalidomide, and the ZF degrons of IKZF1 or ZNF692 showed that the drug–CRBN binding interface can accommodate diverse ZF degrons, and this finding was supported by computational docking and in vitro binding assays that indicated that many ZFs can weakly bind the drug–CRBN interface. Screening additional thalidomide analogues with chemical modifications at the ZF–drug–CRBN interface uncovered two thalidomide-related compounds that allowed degradation of different C2H2 ZF degrons not destabilized by pomalidomide. Taken together, these findings suggest that chemical modification of thalidomide analogues may allow for selective degradation of ZF targets, which may facilitate therapeutic targeting C2H2 ZF transcription factors.
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