Identification of small molecule degraders of XPB for inflammatory diseases

National Center For Advancing Translational Sciences

Investigators

Abstract

During this period, the collaborative team completed high-throughput screening of more than 8,000 biologically active molecules to identify compounds that induce degradation of the XPB protein. Machine-learning modeling based on qHTS data as well as structure-based virtual screening were performed for the entire NCATS diversity library. Several interesting chemotypes of compounds emerged from VS showed either degradation or binding activities in the Hibit and competition assays. The mechanism of action of top actives was examined using several approaches combining affinity-based probes and proteomic methods. Further validation and characterized of the hits with analog expansion and SAR studies are underway.