Thalidomide was originally developed in 1954 as a
sedative that was commonly used to ameliorate
morning sickness. However,
thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g.
phocomelia and amelia), affecting ≈ 10,000 children worldwide in the late 1950s and early 1960s.
Thalidomide is now recognized as a clinically effective, albeit strictly restricted,
drug for the treatment of
leprosy and
multiple myeloma. Investigators have studied
thalidomide teratogenicity for half a century, proposing over 30 hypotheses to account for its actions. Among these, the anti-angiogenesis and oxidative stress models have gained widespread support. Nonetheless, the precise molecular mechanisms and direct targets of
thalidomide have not heretofore been elucidated. We developed
ferrite-
glycidyl methacrylate beads that enable magnetic separation and efficient purification of
ligand-binding molecules; the beads were recently employed to identify cereblon as a primary target of
thalidomide. Cereblon forms an
E3 ubiquitin ligase complex with DDB1, Cul4A, and Roc1, which is important for the expression of
fibroblast growth factor 8, an essential regulator of limb development. Expression of a
drug binding-deficient mutant of cereblon suppressed
thalidomide-induced effects in zebrafish and chicks. This suggests that
thalidomide downregulates
fibroblast growth factor 8 expression and induces limb malformation by binding to wild-type cereblon, inhibiting the function of the associated
E3 ubiquitin ligase. The present review summarizes the teratogenicity of
thalidomide, including existing models for its mode of action, and discusses the identification of cereblon as a key molecule for deciphering the longstanding mystery of
thalidomide teratogenicity.