AN ‘UNDRUGGABLE’ GROUP OF PROTEINS
Most FDA-approved small molecule drugs inhibit enzymes – biology’s protein machines that catalyze chemical reactions. However, many proteins in biology are not enzymes, but they nonetheless play critical roles in health and disease. Among these, transcription factors are particularly interesting drug targets because they act as the on/off switches of gene expression, processes that can cause developmental diseases and cancer when they go wrong.
Until recently, transcription factors have been considered ‘undruggable’ because they lack catalytic active sites for drugs to bind. But in 2014, thalidomide and its analogs – important treatments for multiple myeloma and other blood cancers – were found to inactivate transcription factors using a previously unknown mode of action. These drugs did not inhibit the function of their target proteins, but instead recruited them to an E3 ubiquitin ligase, which flags proteins as garbage causing their removal by the waste disposal system of the cell.
In their recent study, published in Science, Thomä’s and Ebert’s teams have explored whether other transcription factors could be degraded by a similar mechanism. Their results show that modifications to thalidomide result in degradation of different zinc finger transcription factors – a first step towards