Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
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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
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Journal ArticleDOI
Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation
Michael J Bond,Craig M. Crews +1 more
TL;DR: Improved technologies are enabling the development of ligands for “undruggable” proteins and the recruitment of new E3 ligases and enhanced computing power will expedite identification of active degraders.
Journal ArticleDOI
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction.
Kyle R. Simonetta,Joshua Taygerly,Kathleen Boyle,Stephen E. Basham,Chris Padovani,Yan Lou,Thomas Cummins,Stephanie L. Yung,Szerenke Kiss von Soly,Frank Kayser,John Kuriyan,Michael Rape,Mario G. Cardozo,Mark Gallop,Neil Bence,Paul A. Barsanti,Anjanabha Saha +16 more
TL;DR: The prospective discovery of small molecule ‘molecular glue’ that inserts into a naturally occurring E3 ligase-substrate interface leading to degradation of substrate protein is reported, providing a paradigm for the development of small molecules degraders targeting hard-to-drug proteins.
Journal ArticleDOI
Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein
TL;DR: It is demonstrated that induced SHP2 degradation is a very effective approach to inhibit the function of SHP1 and may lead to the development of a new class of therapies for cancers and other human diseases.
Journal ArticleDOI
The PROTACtable genome
Melanie Schneider,Chris J Radoux,Andrew Hercules,David Ochoa,Ian Dunham,Lykourgos-Panagiotis Zalmas,Gerhard Hessler,Sven Ruf,Veerabahu Shanmugasundaram,Michael M. Hann,Pamela Thomas,Markus A. Queisser,Andrew B. Benowitz,Kris Brown,Andrew R. Leach +14 more
TL;DR: In this article, the tractability of PROTAC-targeting chimeras is assessed using a series of criteria based on data and information from a diverse range of relevant publicly available resources.
Journal ArticleDOI
Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery.
TL;DR: A review of molecular glue degraders for targeted protein degradation can be found in this paper, where the authors highlight the recent advances in molecular glues and discuss the challenges in developing molecular glue into therapeutic agents.
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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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