PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
Michele Pagano ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

scholarly journals PHOTACs enable optical control of protein degradation

2020 ◽  
Vol 6 (8) ◽  
pp. eaay5064 ◽  
Author(s):  
Martin Reynders ◽  
Bryan S. Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Modular Approach ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Precision Therapeutics

PROTACs (PROteolysis TArgeting Chimeras) are bifunctional molecules that target proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins. We now introduce photoswitchable PROTACs that can be activated with the spatiotemporal precision that light provides. These trifunctional molecules, which we named PHOTACs (PHOtochemically TArgeting Chimeras), consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated with different wavelengths of light. Our modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.

scholarly journals Chaperone-E3 Ligase Complex HSP70-CHIP Mediates Ubiquitination of Ribosomal Protein S3

2018 ◽  
Vol 19 (9) ◽  
pp. 2723 ◽  
Author(s):  
Inwoo Hwang ◽  
Sung-Woo Cho ◽  
Jee-Yin Ahn
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
E3 Ligase ◽  
Interacting Protein ◽  
Akt Activation ◽  
Protein Levels ◽  
40S Ribosomal Subunit ◽  
Subsequent Degradation ◽  
Ribosomal Protein S3

In addition to its role in ribosome biogenesis, ribosomal protein S3 (RPS3), a component of the 40S ribosomal subunit, has been suggested to possess several extraribosomal functions, including an apoptotic function. In this study, we demonstrated that in the mouse brain, the protein levels of RPS3 were altered by the degree of nutritional starvation and correlated with neuronal apoptosis. After endurable short-term starvation, the apoptotic function of RPS3 was suppressed by Akt activation and Akt-mediated T70 phosphorylation, whereas after prolonged starvation, the protein levels of RPS3 notably increased, and abundant neuronal death occurred. These events coincided with ubiquitination and subsequent degradation of RPS3, controlled by HSP70 and the cochaperone E3 ligase: carboxy terminus of heat shock protein 70-interacting protein (CHIP). Thus, our study points to an extraribosomal role of RPS3 in balancing neuronal survival or death depending on the degree of starvation through CHIP-mediated polyubiquitination and degradation.

The Present and Future of Novel Protein Degradation Technology

2019 ◽  
Vol 19 (20) ◽  
pp. 1784-1788 ◽  
Author(s):  
Liwen Xia ◽  
Wei Liu ◽  
Yinsen Song ◽  
Hailiang Zhu ◽  
Yongtao Duan
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Vital Role ◽  
Therapeutic Modality ◽  
Bifunctional Molecules ◽  
Subsequent Degradation ◽  
Ubiquitin Proteasome ◽  
Future Direction ◽  
Novel Protein

Proteolysis targeting chimeras (PROTACs), as a novel therapeutic modality, play a vital role in drug discovery. Each PROTAC contains three key parts; a protein-of-interest (POI) ligand, a E3 ligase ligand, and a linker. These bifunctional molecules could mediate the degradation of POIs by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS). With several advantages over other therapeutic strategies, PROTACs have set off a new upsurge of drug discovery in recent years. ENDTAC, as the development of PROTACs technology, is now receiving more attention. In this review, we aim to summarize the rapid progress from 2018 to 2019 in protein degradation and analyze the challenges and future direction that need to be addressed in order to efficiently develop potent protein degradation technology.

scholarly journals A Phenotypic Approach for the Identification of New Molecules for Targeted Protein Degradation Applications

2021 ◽  
pp. 247255522110175
Author(s):  
Peter Stacey ◽  
Hannah Lithgow ◽  
Xiao Lewell ◽  
Agnieszka Konopacka ◽  
Stephen Besley ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Protein Degradation ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Von Hippel Lindau ◽  
Protein Levels ◽  
New Strategy ◽  
Cellular Context

Targeted protein degradation is an emerging new strategy for the modulation of intracellular protein levels with applications in chemical biology and drug discovery. One approach to enable this strategy is to redirect the ubiquitin–proteasome system to mark and degrade target proteins of interest (POIs) through the use of proteolysis targeting chimeras (PROTACs). Although great progress has been made in enabling PROTACs as a platform, there are still a limited number of E3 ligases that have been employed for PROTAC design. Herein we report a novel phenotypic screening approach for the identification of E3 ligase binders. The key concept underlying this approach is the high-throughput modification of screening compounds with a chloroalkane moiety to generate HaloPROTACs in situ, which were then evaluated for their ability to degrade a GFP-HaloTag fusion protein in a cellular context. As proof of concept, we demonstrated that we could generate and detect functional HaloPROTACs in situ, using a validated Von Hippel–Lindau (VHL) binder that successfully degraded the GFP-HaloTag fusion protein in living cells. We then used this method to prepare and screen a library of approximately 2000 prospective E3 ligase-recruiting molecules.

scholarly journals Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation

2018 ◽  
Vol 294 (7) ◽  
pp. 2436-2448 ◽  
Author(s):  
Laura J. Sharpe ◽  
Vicky Howe ◽  
Nicola A. Scott ◽  
Winnie Luu ◽  
Lisa Phan ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Protein Levels

scholarly journals Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone

2020 ◽  
Author(s):  
Bingqi Tong ◽  
Mai Luo ◽  
Yi Xie ◽  
Jessica Spradlin ◽  
John A. Tallarico ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Protein Degradation ◽  
Small Molecules ◽  
Small Molecule ◽  
E3 Ligase ◽  
E3 Ligases ◽  
Protein Levels ◽  
Nrf2 Activator

<p>Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules (i.e. PROTACs). E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the >500 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3’s has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-NRF2 activator bardoxolone to a BRD4 inhibitor JQ1. Notably, this work reports the first covalent, reversible E3 ligase recruiter for TPD applications. </p>

scholarly journals Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone

2020 ◽  
Author(s):  
Bingqi Tong ◽  
Mai Luo ◽  
Yi Xie ◽  
Jessica Spradlin ◽  
John A. Tallarico ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Protein Degradation ◽  
Small Molecules ◽  
Small Molecule ◽  
E3 Ligase ◽  
E3 Ligases ◽  
Protein Levels ◽  
Nrf2 Activator

<p>Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules (i.e. PROTACs). E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the >500 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3’s has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-NRF2 activator bardoxolone to a BRD4 inhibitor JQ1. Notably, this work reports the first covalent, reversible E3 ligase recruiter for TPD applications. </p>

scholarly journals Perspectives on the development of first-in-class protein degraders

2021 ◽  
Author(s):  
Kalyn M Rambacher ◽  
Matthew F Calabrese ◽  
Masaya Yamaguchi
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Target Protein ◽  
Protein Homeostasis ◽  
Recent Advances ◽  
Subsequent Degradation ◽  
Ubiquitin Proteasome

Targeted protein degradation is a broad and expanding field aimed at the modulation of protein homeostasis. A focus of this field has been directed toward molecules that hijack the ubiquitin proteasome system with heterobifunctional ligands that recruit a target protein to an E3 ligase to facilitate polyubiquitination and subsequent degradation by the 26S proteasome. Despite the success of these chimeras toward a number of clinically relevant targets, the ultimate breadth and scope of this approach remains uncertain. Here we highlight recent advances in assays and tools available to evaluate targeted protein degradation, including and beyond the study of E3-targeted chimeric ligands. We note several challenges associated with degrader development and discuss various approaches to expanding the protein homeostasis toolbox.

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