Monitoring and deciphering protein degradation pathways inside cells

Publication date: Available online 19 December 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Danette L. Daniels, Kristin M. Riching, Marjeta UrhA new series of therapeutic modalities resulting in degradation of target proteins, termed proteolysis targeting chimeras (PROTACs), hold significant therapeutic potential with possible prolonged pharmacodynamics, improved potency, and ability to target proteins previously thought of as “undruggable”. PROTACs are heterobifunctional small molecules consisting of a target binding handle bridged via a chemical linker to an E3 ligase handle which recruit the E3 ligase and ubiquitin machinery to target proteins, resulting in subsequent ubiquitination and degradation of the target. With the generation of small molecule PROTAC compound libraries for drug discovery, it becomes essential to have sensitive screening technologies to rapidly profile activity and have assays which can clearly inform on performance at the various cellular steps required for PROTAC-mediated degradation. For PROTAC compounds, this has been particularly challenging using either biochemical or cellular assay approaches. Biochemical assays are highly informative for the first part of the degradation process, including optimization of compound binding to targets and interrogation of target:PROTAC:E3 ligase ternary complex formation, but struggle with the remaining steps; recruitment of ternary complex into larger active E3 ligase complexes, ubiquitination,...

Source: Drug Discovery Today: Technologies - December 19, 2018 Category: Drugs & Pharmacology Source Type: research