P63 shows to be a Cereblon substrate involved in thalidomide teratogenicity
During the last decades, drug testing has been continuously improved as new aspects of biology and drug-effects where discovered. Although many times, improvements came after discovering catastrophic effects nobody thought about. This happened in the famous thalidomide disaster, which is considered as one of the darkest episodes in pharmaceutical research history.
The drug was marketed as an anti-nausea and sleeping pill safe for pregnant women. However, it has grave teratogenic effects and is responsible for thousands of babies worldwide to have been born with malformed limbs. Due to this, teratogenicity testing has been reinforced as obligatory in drug research. Curiously, more than 50 years later, the precise mechanism of action for thalidomide is still not entirely known, conducting to over 2000 research papers to date. Research efforts focusing on determining how thalidomide causes teratogenic defects are also used to research for safer isoforms and derivates.
One of the main theories is its inhibition of cereblon, a ubiquitin ligase that regulates fibroblast growth factors 8 and 10. This theory now sees new results, as researchers of the Tokyo Medical University and the University of Milan show new results in zebrafish that elucidate how p63 is a thalidomide substrate related to the teratogenic effects. The extense roles of p63 proteins are well-conserved between humans and zebrafish, permitting them to get the full potential of the model. The research showed how both gene-products, ∆Np63α and TAp63α are CRL4CRBN new substrates and where responsible for different defects, which shows that they may have distinct roles in development. z∆Np63α proved to be responsible for thalidomide-induced fin(limbs)-defects, while zTAp63α mediated the thalidomide-induced otic-defects.
We hope that more Cereblon substrates will soon be found, as well as the molecular mechanisms by which these compounds exert teratogenic effects, as thalidomide-based drugs targeting Cereblon are of growing importance because of the results derivates show in cancers and inflammatory diseases. Understanding the mechanisms in depth may unlock the full drug's potential.
By: Marina Müller (ZeClinics)
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