An international collaborative research group at Tokyo Medical University, Tokyo Institute of Technology, and the University of Milan, Italy, has revealed that the cause of malformations by salidamide is the degradation of a protein called p63.
Thalidomide, which is teratogenic to the fetal body, was known in the 1960s worldwide phytotoxicity incidents, but was later found to have excellent therapeutic effects on some intractable diseases, and is now subject to national regulations. A strict prescription is made based on this.Research and development of drugs with a thalidomide skeleton are being vigorously pursued, but thalidomide compounds without teratogenicity have not yet been found.
In 2010, the researchers found that the major target factor for thalidomide was a protein called cereblon, and in subsequent studies, binding of thalidomide compounds to cereblon changed the substrate specificity of cereblon, usually. It was clarified that proteins that are not degraded will be degraded.And now, among these drug-dependently degraded proteins, he found that the p63 protein is involved in the teratogenicity of thalidomide.
There are two types of p63, large and small, and the smaller one plays an important role in the formation of limbs and the larger one plays an important role in the formation of ears during fetal development.When analyzed using zebrafish, a vertebrate model organism, the researchers found that thalidomide binding to cereblon induces both large and small degradation of the p2 protein, resulting in malformations of the limbs and ears. It became clear.
Since this study revealed that the cause of the side effects of thalidomide is the degradation of p63, it is expected that a safe new drug that does not induce the degradation of p63 will be developed in the future.
Paper information:[Nature Chemical Biology] p63 is a cereblon substrate involved in thalidomide teratogenicity
