Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN

Abstract

Thalidomide-targeted degradation Thalidomide and its analogs improve the survival of patients with multiple myeloma and other blood cancers. Previous work showed that the drugs bind to the E3 ubiquitin ligase Cereblon, which then targets for degradation two specific zinc finger (ZF) transcription factors with a role in cancer development. Sievers et al. found that more ZF proteins than anticipated are destabilized by thalidomide analogs. A proof-of-concept experiment revealed that chemical modifications of thalidomide can lead to selective degradation of specific ZF proteins. The detailed information provided by structural, biochemical, and computational analyses could guide the development of drugs that target ZF transcription factors implicated in human disease. Science , this issue p. eaat0572