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

Poster Board Number: A231

Yan Zhang (University of Texas), Brenda Medellin (University of Texas), Wanjie Yang (University of Texas), Dio Siegel (University of California, San Diego)

The repressor element-1 silencing transcription factor (REST) represses neuronal gene expression, whose dysregulation is implicated in brain tumors and neurological diseases. 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 inhibition 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.

National Institutes of Health (R01 GM104896 and 125882 to Y.Z.), Alzheimers Drug Discovery Foundation Grant, and Welch Foundation (F-1778 to Y.Z.).



Docking model of covalent inhibition of SCP1 by T-65.