Targeting the Spliceosomal Protein USP39 Through Allosteric Ligands and PROTAC-Induced Degradation.

ABSTRACT: The precise regulation of gene expression is fundamental to cellular homeostasis and diversity. Dysregulation of splicing has been implicated in a range of diseases, including cancer and neurodegeneration. Ubiquitin-specific protease 39 (USP39), an essential spliceosome component lacking enzymatic activity, has remained an elusive target for pharmacological intervention. Here, we report the discovery of small-molecule ligands that selectively engage with USP39 through a thiazole scaffold, primarily interacting with its zinc finger domain. Guided by AlphaFold-based structure-activity relationship studies, we designed and optimized proteolysis-targeting chimeras (PROTACs), culminating in the development of USP39_PROTAC_V1, which harnesses the von Hippel-Lindau (VHL) E3 ubiquitin ligase for t

SUBMITTER: Schafer D 

PROVIDER: S-EPMC12851022 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature