The drug thalidomide was recalled in the 1960s because it caused devastating defects in newborns, but at the same time it was widely used to treat multiple sclerosis and other blood cancers, and can, with its chemical relatives, promote cellular destruction of two specific proteins that are members of a family of conventional “drug-free” proteins (transcription factors) that have a specific molecular pattern, the C2H2 zinc finger motif.

In a recent study published in the international journal Science, scientists from the MIT Boulder Institute and other institutions found that thalidomide and related drugs may provide a starting point for researchers to develop a new type of anti-cancer compound that is expected to target approximately 800 transcription factors that share the same motif. Transcription factors bind to DNA and coordinate the expression of multiple genes, which are often specific to particular cell types or tissues; these proteins are associated with many cancers when they go awry, but researchers have found that it may be difficult to target them for drug development because transcription factors often miss the sites where drug molecules come into direct contact with them.

Thalidomide and its chemical relatives pomalidomide and lenalidomide can indirectly attack their targets by enlisting a protein called cereblon - two transcription factors that possess C2H2 ZF: IKZF1 and IKZF3. Cereblon is a specific molecule called E3 ubiquitin ligase and can label specific proteins for degradation by the cellular circulatory system. In the absence of thalidomide and its relatives, cereblon ignores IKZF1 and IKZF3; in their presence, it promotes recognition of these transcription factors and their labeling for processing.

A new role for this ancient drug

The human genome is capable of encoding approximately 800 transcription factors, such as IKZF1 and IKZF3, which are able to tolerate certain mutations in the C2H2 ZF motif; identifying specific factors that can aid in drug development can help researchers discover if other similar transcription factors are susceptible to thalidomide-like drugs. If any thalidomide-like drug was present, the researchers could determine the precise C2H2 ZF properties observed by protein cereblon, which then screened for the ability of thalidomide, pomalidomide and lenalidomide to induce degradation of 6,572 specific C2H2 ZF motif variants in cellular models. Finally the researchers identified six C2H2 ZF-containing proteins that would become sensitive to these drugs, four of which were not previously considered to be targets for thalidomide and its relatives.

The researchers then performed functional and structural characterization of IKZF1 and IKZF3 to better understand the mechanisms of interaction between the transcription factors, cereblon and their thalidomide. Besides, they also ran 4,661 mutational computer models to see if other transcription factors could be predicted to dock with cereblon in the presence of the drug. The researchers indicated that suitably modified thalidomide-like drugs should induce cereblon to tag specific isoforms of the C2H2 ZF transcription factor to repurpose it.