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New thalidomide nuance revealed

Drug degrades transcription factor in limb development, but further work needed to confirm relevance

by Cici Zhang
August 19, 2018 | A version of this story appeared in Volume 96, Issue 33

A structure of thalidomide is shown here.

The problematic morning-sickness drug thalidomide caused birth defects in thousands of children during the 1950s. Thalidomide was recently repurposed as an anticancer treatment, and progress has been made to understand its therapeutic actions, but how it led to developmental defects decades ago remains unclear. Now, a team led by Eric Fischer of Dana-Farber Cancer Institute has evidence that thalidomide might induce teratogenicity by interacting with a key protein in its anticancer mechanism (eLife 2018, DOI: 10.7554/elife.38430). Previous research found that thalidomide binds to cereblon, a component of a ubiquitin ligase that’s involved in marking proteins for degradation. In the new study, Fischer and coworkers did a proteomics screen of human embryonic stem cells and identified a potential binding target of the thalidomide-cereblon complex that might contribute to the compound’s teratogenic actions. They found thalidomide degraded a transcription factor called SALL4. In humans, mutations of SALL4 lead to a limb deformation syndrome that resembles thalidomide-induced birth defects. Fischer says that though the evidence suggests SALL4 is a major target in thalidomide’s pathogenesis, there could be other targets and combined effects of multiple targets at play. His lab plans to perform animal studies to further examine the mechanism.


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