Interrogating the Ubiquitin landscape: integrated drug discovery platforms for RING E3 ligases and chemical biology tools for Ubiquitin-like modifiers

Abstract

This dissertation describes the development of integrated drug discovery platforms and chemical biology tools to study RING E3 ligases and Ubiquitin-like modifiers. The work presented herein is divided into two distinct yet complementary scientific endeavors, highlighting two converging themes in modern chemical biology: the development of small-molecules targeting RING E3 ligases and the creation of a synthetic toolkit to dissect the functions of the understudied Ubl FUBI. By employing a multidisciplinary approach that combines high-throughput screening, computational modeling, and total chemical synthesis, this work establishes a robust framework for addressing the challenges associated with targeting “undruggable” scaffolds and interrogating understudied Ubl signaling pathways.