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Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects.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.
Highlights
Thalidomide (Figure 1A) was first developed by Chemie Grünenthal (West Germany) in 1957 and was soon in use worldwide as a sedative
We introduce the basic functions of CRBN and discuss our current understanding of the molecular mechanisms of thalidomide, mainly focusing on its teratogenicity
These findings demonstrated that CRBN was a primary target of thalidomide and critically involved in thalidomide teratogenicity
Summary
Thalidomide (Figure 1A) was first developed by Chemie Grünenthal (West Germany) in 1957 and was soon in use worldwide as a sedative. As the therapeutic efficacy of thalidomide was demonstrated, many thalidomide derivatives with greater potency were developed, yet the molecular mechanisms underlying the effects of thalidomide, such as inhibition of oxidative stress or angiogenesis, remained uncertain [22,23,24,25]. ((II)) ddBBEETT11,, ccoommppoosseedd ooff JJQQ11 ((aa BBRRDD44 iinnhhiibbiittoorr)) aanndd tthhaalliiddoommiiddee. 2. TeArastothgeenthicerAapcteiuvtiitcyeoffif cTahcyaloidf othmailiddeomide was greater potency were developed, yet the molecular demonstrated, many thalidomide derivatives with mechanisms underlying the effects of thalidomide, such Washinenhipbriteigonaonftowxiodmateinvetosotrkestshaolridaonmgioidgeenbestwis,ereenmdaaiyne2d0 uancdedrtaayin3[62a2f–t2e5r]f.eTrthileizmatoiostni,mmpuolrttiapnlet qbuirethstiodnefwecatss toocidcuenrrteifdy t[h2e9]d.irAectstianrggleet otfabthleatlid(5o0mimdeg.) of thalidomide was enough to induce deveAlopdmeceandteaal gdoe,fewcetsid[2e9n]t.iAfiebdroceardebsploenct(rCuRmBNof)baisrtahpdriemfeacrtys wtaargserteopfotrhteadlid, ionmcliuddeitnegramtoaglefonrimcitayti[o2n6s]. We introduce the basic functions of CRBN and discuss our current understanding of the molecular mechanisms of thalidomide, mainly focusing on its teratogenicity
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