Birth defects The drug
thalidomide binds to cereblon and changes which substrates can be degraded by it, which leads to an antiproliferative effect on myeloma cells and possibly the
teratogenic effect on
fetal development. Thalidomide was used as a treatment for
morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. It is estimated that 10,000 to 20,000 children were affected. However, the idea that cereblon modulation is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that
pomalidomide (a more potent thalidomide analogue) does not cause teratogenic effects in these same model systems even though it binds with cereblon more strongly than thalidomide.
Intellectual disability Mutations in the CRBN gene are associated with
autosomal recessive nonsyndromic
intellectual disability, These molecules, termed
proteolysis targeting chimeras (PROTACs) or protein degraders, recruit CRBN to a protein of interest, leading to its ubiquitination and subsequent degradation. This technology is being explored in clinical trials by a number of biotechnology companies such as Arvinas, C4 Therapeutics, and Kymera Therapeutics. == References ==