Identification of a Primary Target of Thalidomide Teratogenicity

TLDR

Thalidomide, once widely prescribed to pregnant women, caused severe birth defects, yet its mechanism of limb malformation remains unclear despite continued use for leprosy and multiple myeloma. Thalidomide binds cereblon, a component of an E3 ubiquitin ligase complex with DDB1 and Cul4A, blocking its activity and disrupting limb outgrowth and Fgf8 expression in zebrafish and chicks. The study identifies cereblon as the thalidomide‑binding protein, establishing a mechanistic basis for its teratogenicity and guiding the design of safer thalidomide analogs.

Abstract

Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.