Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TLDR
Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.Abstract:
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.read more
Citations
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A General Strategy for the Preparation of Thalidomide-Conjugate Linkers
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Book ChapterDOI
Kinetic Detection of E3:PROTAC:Target Ternary Complexes Using NanoBRET Technology in Live Cells
TL;DR: In this article, cellular assays utilizing NanoBRET technology for the study of ternary complexes, showing examples with two most popular PROTAC E3 ligase components, VHL (von Hippel-Lindau disease tumor suppressor) and CRBN (Cereblon).
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Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary
TL;DR: This review provides an overview of newly emerging antiviral strategies, including proteolysis targeting chimera (PROTAC), ribonuclease targeting Chimera (RIBotAC), targeted covalent inhibitors, topology-matching design and antiviral drug delivery system.
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Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos.
TL;DR: A first-in-class NSD2 proteolysis targeting chimera (PROTAC) degrader, 9, and two structurally similar controls, 17 and 18, with diminished binding to the cereblon (CRBN) E3 ligase and N SD2, respectively, are discovered and are valuable chemical tools for exploring the roles of NSD 2 in health and disease.
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Role of UPP pathway in amelioration of diabetes-associated complications.
Amit Gupta,Tapan Behl,Lotfi Aleya,Md. Habibur Rahman,Md. Habibur Rahman,Harlokesh Narayan Yadav,Giridhari Pal,Ishnoor Kaur,Sandeep Arora +8 more
TL;DR: In this paper, the role of ubiquitin's is not limited to neurodegenerative disorders, but also plays a critical role in progression of diabetes including obesity, insulin resistance, and various neurogenerative disorders but it also targets proteasomal degradation including mediation of cellular signaling pathways.
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TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
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