Molecular Mechanisms of the Teratogenic Effects of Thalidomide

Abstract

Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity.

A drug repositioning success: The repositioned therapeutic applications and mechanisms of action of thalidomide

“…27 Investigators believed that the effects responsible for teratogenicity also represented potential mechanisms for cancer treatment. 12 In 2006, the FDA approved the use of thalidomide for newly diagnosed multiple myeloma under strict control. 6,18,31…”

“…In rabbits, fetuses from thalidomide treated females were noted to have pronounced abnormalities in long bone formation resembling the thalidomide-induced embryopathy seen in the human fetus. 11–13…”

Thal protects against paraquat‐induced lung injury through a microRNA‐141/HDAC6/IκBα‐NF‐κB axis in rat and cell models

“…41 In addition, bGFG is the mostly studied fibrosis-related factor, 42,43 and PQ has been reported to enhance bGFG expression and promote fibrosis in rat lungs, 44 while thalidomide has been reported to inhibit bFGF expression in rats, 45 which was partially in line with our findings. Moreover, considering the teratogenicity 9 and potential side-effects of thalidomide, specifically, rats and cells were treated with thalidomide alone, and it was found that alone administration of thalidomide did not affect the lungs and cells.…”

“…Thalidomide was first developed in 1957 and widely served as a sedative worldwide, but it was banned from the market soon in 1961 due to its side-effect of teratogenicity. 9 Despite this, thalidomide is a well-known immunomodulatory compound that has been noted as a potential drug for autoimmune diseases, 10 angiogenesis-related diseases including cancer 11 and inflammation control. 12,13 Importantly, the anti-inflammatory effect of thalidomide in PQ-induced pulmonary injury has been witnessed in a mouse model.…”

A tale of two tails - efficient profiling of protein degraders by specific functional and target engagement readouts

“…However, since then, thalidomide and its close analogs have been repurposed as potent anticancer agents 9,10 . Given the excitement regarding thalidomide's anticancer activity, particularly for multiple myeloma, medicinal chemistry efforts were undertaken to develop related compounds preserving these beneficial activities 11 . In 2010, a major step towards understanding IMiD action was made when cereblon (CRBN) was identified as a major target driving the thalidomide teratogenicity 12 .…”