Recent advances in the molecular mechanism of thalidomide teratogenicity

Abstract

Thalidomide was first marketed in 1957 but soon withdrawn because of its notorious teratogenicity. Studies on the mechanism of action of thalidomide revealed the pleiotropic properties of this class of drugs, including their anti-inflammatory, antiangiogenic and immunomodulatory activities. Based on their notable activities, thalidomide and its analogues, lenalidomide and pomalidomide, have been repurposed to treat erythema nodosum leprosum, multiple myeloma and other haematological malignancies. Thalidomide analogues were recently found to hijack CRL4^CRBN ubiquitin ligase to target a number of cellular proteins for ubiquitination and proteasomal degradation. Thalidomide-mediated degradation of SALL4 and p63, transcription factors essential for embryonic development, very likely plays a critical role in thalidomide embryopathy. In this review, we provide a brief retrospective summary of thalidomide-induced teratogenesis, the mechanism of thalidomide activity, and the latest advances in the molecular mechanism of thalidomide-induced birth malformations.

Keywords: CRL4(CRBN); SALL4; Teratogenicity; Thalidomide; Ubiquitination; p63.