Targeted Covalent Inhibition of Small CTD Phosphatase 1 to Promote the Degradation of the REST Transcription Factor in Human Cells

The repressor element-1 silencing
transcription factor (REST) represses
neuronal gene expression, whose dysregulation is implicated in brain
tumors and neurological diseases. A high level of REST protein drives
the tumor growth in some glioblastoma cells. While transcription factors
like REST are challenging targets for small-molecule inhibitors, the
inactivation of a regulatory protein, small CTD phosphatase 1 (SCP1),
promotes REST degradation and reduces transcriptional activity. This
study rationally designed a series of α,β-unsaturated
sulfones to serve as potent and selective covalent inhibitors against
SCP1. The compounds inactivate SCP1 via covalent modification of Cys181
located at the active site entrance. Cellular studies showed that
the inhibitors inactivate SCP1 in a time- and dose-dependent manner
with an EC50 ∼1.5 μM, reducing REST protein
levels and activating specific REST-suppressed genes. These compounds
represent a promising line of small-molecule inhibitors as a novel
lead for glioblastoma whose growth is driven by REST transcription
activity.