The Experts below are selected from a list of 253836 Experts worldwide ranked by ideXlab platform
Craig M Crews - One of the best experts on this subject based on the ideXlab platform.
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Targeted Protein Degradation: expanding the toolbox.
Nature reviews. Drug discovery, 2019Co-Authors: Matthieu Schapira, Matthew F. Calabrese, Alex N. Bullock, Craig M CrewsAbstract:Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted Protein Degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted Protein Degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted Protein Degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.
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Targeted Protein Degradation: elements of PROTAC design.
Current Opinion in Chemical Biology, 2019Co-Authors: Stacey-lynn Paiva, Craig M CrewsAbstract:Targeted Protein Degradation using Proteolysis Targeting Chimeras (PROTACs) has emerged as a novel therapeutic modality in drug discovery. PROTACs mediate the Degradation of select Proteins of interest (POIs) by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent Degradation by the 26S proteasome. This hijacking mechanism has been used to degrade various types of disease-relevant POIs. In this review, we aim to highlight the recent advances in targeted Protein Degradation and describe the challenges that need to be addressed in order to efficiently develop potent PROTACs.
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Targeted Protein Degradation by PROTACs.
Pharmacology & Therapeutics, 2017Co-Authors: Taavi K. Neklesa, James D Winkler, Craig M CrewsAbstract:Abstract Targeted Protein Degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a disease-causing Protein. PROTAC molecules are bifunctional small molecules that simultaneously bind a target Protein and an E3-ubiquitin ligase, thus causing ubiquitination and Degradation of the target Protein by the proteasome. Like small molecules, PROTAC molecules possess good tissue distribution and the ability to target intracellular Proteins. Herein, we highlight the advantages of Protein Degradation using PROTACs, and provide specific examples where Degradation offers therapeutic benefit over classical enzyme inhibition. Foremost, PROTACs can degrade Proteins regardless of their function. This includes the currently “undruggable” proteome, which comprises approximately 85% of all human Proteins. Other beneficial aspects of Protein Degradation include the ability to target overexpressed and mutated Proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, an exquisitely potent molecules with a high degree of Degradation selectivity can be designed. Impressive preclinical in vitro and in vivo PROTAC data have been published, and these data have propelled the development of clinically viable PROTACs. With the molecular weight falling in the 700–1000 Da range, the delivery and bioavailability of PROTACs remain the largest hurdles on the way to the clinic. Solving these issues and demonstrating proof of concept clinical data will be the focus of many labs over the next few years.
Tobias C Walther - One of the best experts on this subject based on the ideXlab platform.
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a systematic Protein turnover map for decoding Protein Degradation
Cell Reports, 2020Co-Authors: Romain Christiano, S Kabatnik, Niklas Mejhert, Robert V Farese, Henning Arlt, Zon Weng Lai, Tobias C WaltherAbstract:Summary Protein Degradation is mediated by an expansive and complex network of Protein modification and Degradation enzymes. Matching Degradation enzymes with their targets and determining globally which Proteins are degraded by the proteasome or lysosome/vacuole have been a major challenge. Furthermore, an integrated view of Protein Degradation for cellular pathways has been lacking. Here, we present an analytical platform that combines systematic gene deletions with quantitative measures of Protein turnover to deconvolve Protein Degradation pathways for Saccharomyces cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary Degradation routes for most Proteins. We further mined this T-MAP to identify new substrates of ER-associated Degradation (ERAD) involved in sterol biosynthesis and to uncover regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes, including mammalian systems.
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a systematic Protein turnover map for decoding Protein Degradation
bioRxiv, 2020Co-Authors: Romain Christiano, S Kabatnik, Niklas Mejhert, Robert V Farese, Tobias C WaltherAbstract:Protein Degradation is mediated by an expansive and complex network of Protein modification and Degradation enzymes. Matching Degradation enzymes with their targets and determining globally which Proteins are degraded by the proteasome or lysosome/vacuole has been a major challenge. Further, an integrated view of Protein Degradation for cellular pathways has been lacking. Here we present a novel analytical platform that combines systematic gene deletions with quantitative measures of Protein turnover to deconvolve Protein Degradation pathways for S. cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary Degradation routes for most Proteins. We further mined this T-MAP to identify new substrates of ER-associated Degradation (ERAD) involved in sterol biosynthesis and to uncover novel regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes and systems, including mammalian systems. One Sentence Summary A systematic, global map of Protein turnover for a large set of yeast mutants reveals scope and specificity of Degradation pathways and identifies novel regulatory nodes for lipid metabolism.
Robert V Farese - One of the best experts on this subject based on the ideXlab platform.
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a systematic Protein turnover map for decoding Protein Degradation
Cell Reports, 2020Co-Authors: Romain Christiano, S Kabatnik, Niklas Mejhert, Robert V Farese, Henning Arlt, Zon Weng Lai, Tobias C WaltherAbstract:Summary Protein Degradation is mediated by an expansive and complex network of Protein modification and Degradation enzymes. Matching Degradation enzymes with their targets and determining globally which Proteins are degraded by the proteasome or lysosome/vacuole have been a major challenge. Furthermore, an integrated view of Protein Degradation for cellular pathways has been lacking. Here, we present an analytical platform that combines systematic gene deletions with quantitative measures of Protein turnover to deconvolve Protein Degradation pathways for Saccharomyces cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary Degradation routes for most Proteins. We further mined this T-MAP to identify new substrates of ER-associated Degradation (ERAD) involved in sterol biosynthesis and to uncover regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes, including mammalian systems.
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a systematic Protein turnover map for decoding Protein Degradation
bioRxiv, 2020Co-Authors: Romain Christiano, S Kabatnik, Niklas Mejhert, Robert V Farese, Tobias C WaltherAbstract:Protein Degradation is mediated by an expansive and complex network of Protein modification and Degradation enzymes. Matching Degradation enzymes with their targets and determining globally which Proteins are degraded by the proteasome or lysosome/vacuole has been a major challenge. Further, an integrated view of Protein Degradation for cellular pathways has been lacking. Here we present a novel analytical platform that combines systematic gene deletions with quantitative measures of Protein turnover to deconvolve Protein Degradation pathways for S. cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary Degradation routes for most Proteins. We further mined this T-MAP to identify new substrates of ER-associated Degradation (ERAD) involved in sterol biosynthesis and to uncover novel regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes and systems, including mammalian systems. One Sentence Summary A systematic, global map of Protein turnover for a large set of yeast mutants reveals scope and specificity of Degradation pathways and identifies novel regulatory nodes for lipid metabolism.
Henning Arlt - One of the best experts on this subject based on the ideXlab platform.
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a systematic Protein turnover map for decoding Protein Degradation
Cell Reports, 2020Co-Authors: Romain Christiano, S Kabatnik, Niklas Mejhert, Robert V Farese, Henning Arlt, Zon Weng Lai, Tobias C WaltherAbstract:Summary Protein Degradation is mediated by an expansive and complex network of Protein modification and Degradation enzymes. Matching Degradation enzymes with their targets and determining globally which Proteins are degraded by the proteasome or lysosome/vacuole have been a major challenge. Furthermore, an integrated view of Protein Degradation for cellular pathways has been lacking. Here, we present an analytical platform that combines systematic gene deletions with quantitative measures of Protein turnover to deconvolve Protein Degradation pathways for Saccharomyces cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary Degradation routes for most Proteins. We further mined this T-MAP to identify new substrates of ER-associated Degradation (ERAD) involved in sterol biosynthesis and to uncover regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes, including mammalian systems.
B.-k. Kaang - One of the best experts on this subject based on the ideXlab platform.
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Synaptic Protein Degradation in Memory Reorganization
Advances in experimental medicine and biology, 2012Co-Authors: B.-k. Kaang, Jun-hyeok ChoiAbstract:The ubiquitin-proteasome system (UPS) is a ubiquitous, major pathway of Protein Degradation that is involved in most cellular processes by regulating the abundance of certain Proteins. Accumulating evidence indicates a role for the UPS in specific functions of neurons. In this chapter, we first introduce the role of the UPS in neuronal function and the mechanism of UPS regulation following synaptic activity. Then, we focus on the recently revealed, distinct role of the UPS in the destabilization of a reactivated memory. Finally, we discuss the physiological role of this destabilization process. The reactivated memory may undergo modification from the initial memory depending on the context in which the memory is reactivated, which we will term memory reorganization. We will introduce the role of the Protein Degradation–dependent destabilization process for memory reorganization and suggest a hypothetical model combining the recent findings.
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Protein Degradation during Reconsolidation as a Mechanism for Memory Reorganization.
Frontiers in behavioral neuroscience, 2011Co-Authors: B.-k. Kaang, Jun-hyeok ChoiAbstract:Memory is a reference formed from a past experience that is used to respond to present situations. However, the world is dynamic and situations change, so it is important to update the memory with new information each time it is reactivated in order to adjust the response in the future. Recent researches indicate that memory may undergo a dynamic process that could work as an updating mechanism. This process which is called reconsolidation involves destabilization of the memory after it is reactivated, followed by restabilization. Recently, it has been demonstrated that the initial destabilization process of reconsolidation requires Protein Degradation. Using Protein Degradation inhibition as a method to block reconsolidation, recent researches suggest that reconsolidation, especially the Protein Degradation-dependent destabilization process is necessary for memory reorganization.
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S17-03 Memory reorganization by synaptic Protein Degradation
European Psychiatry, 2009Co-Authors: B.-k. KaangAbstract:An accumulating body of evidence shows that the retrieval process of long-term memory is not static and requires de novo Protein synthesis. Thus long-term memories are dynamic and particularly become fragile during its retrieval. Importantly, memory retrieval is regarded as a step necessary for incorporating new information into preexisting memories. We have examined whether Protein Degradation is involved in the memory reorganization or not. In this presentation I will present the evidence that synaptic Proteins are degraded by polyubiquitination and proteasome pathway in the hippocampus after the retrieval of contextual fear conditioning. In addition, we found that the infusion of a proteasome inhibitor into the hippocampus prevented the memory impairment induced by anisomycin, a Protein synthesis inhibitor. This indicates that ubiquitin/proteasome-dependent Protein Degradation is involved in destabilization processes accompanying the memory retrieval. It also supports our hypothesis that preexisting memory is disrupted by synaptic Protein Degradation before updated memory is strengthened by Protein synthesis. Our data also showed that synaptic Protein Degradation plays a critical role in fear memory extinction, a simple form of memory reorganization. Taken together, synaptic Protein Degradation is critically involved in the reorganization of the preexisting memories.
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synaptic Protein Degradation underlies destabilization of retrieved fear memory
Science, 2008Co-Authors: Suehyun Lee, Jun-hyeok Choi, Nuribalhae Lee, Hyeryeon Lee, Jaeick Kim, Sunlim Choi, Seunghee Lee, Hyoung F Kim, B.-k. KaangAbstract:Reactivated memory undergoes a rebuilding process that depends on de novo Protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting memories. However, little is known about whether or not Protein Degradation is involved in the reorganization of retrieved memory. We found that postsynaptic Proteins were degraded in the hippocampus by polyubiquitination after retrieval of contextual fear memory. Moreover, the infusion of proteasome inhibitor into the CA1 region immediately after retrieval prevented anisomycin-induced memory impairment, as well as the extinction of fear memory. This suggests that ubiquitin- and proteasome-dependent Protein Degradation underlies destabilization processes after fear memory retrieval. It also provides strong evidence for the existence of reorganization processes whereby preexisting memory is disrupted by Protein Degradation, and updated memory is reconsolidated by Protein synthesis.