Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation.

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Martin P Schwalm, Amelie Menge, Lewis Elson, Francesco A Greco, Matthew B Robers, Susanne Müller, Stefan Knapp
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引用次数: 0

Abstract

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development and important tools for target validation. When appropriately optimized, both modalities lead to proteasomal degradation of the protein of interest (POI). Due to the complexity of the induced multistep degradation process, controls for degrader evaluation are critical and commonly used in the literature. However, comparative studies and evaluations of cellular potencies of these control compounds have not been published so far. Here, we investigated a diverse set of ubiquitin pathway inhibitors and evaluated their potency and utility within the CRBN and VHL-mediated degradation pathway. We used the HiBiT system to measure the level of target rescue after treatment with the control compounds. In addition, the cell health was assessed using a multiplexed high-content assay. These assays allowed us to determine nontoxic effective concentrations for control experiments and to perform rescue experiments in the absence of cellular toxicity.

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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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