Ubiquitin‐Independent Degradation: An Emerging PROTAC Approach? DOI Creative Commons
Tiantian Li, Saskia A. Hogenhout, Weijie Huang

et al.

BioEssays, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

ABSTRACT Targeted protein degradation (TPD) has emerged as a highly promising approach for eliminating disease‐associated proteins in the field of drug discovery. Among most advanced TPD technologies, PROteolysis TArgeting Chimera (PROTAC), functions by bringing interest (POI) into proximity with an E3 ubiquitin ligase, leading to (Ub)‐dependent proteasomal degradation. However, designs PROTACs are based on utilization limited number available ligases, which significantly restricts their potential. Recent studies have shown that phytoplasmas, group bacterial plant pathogens, developed several E3‐ and ubiquitin‐independent (UbInPD) mechanisms breaking down host targets. This suggests alternative substrate recruitment TPD. Here, we present existing evidence supports feasibility UbInPD eukaryotic cells propose candidate can serve docking sites development E3‐independent PROTACs.

Language: Английский

Targeted protein degradation directly engaging lysosomes or proteasomes DOI Creative Commons
Jiseong Kim, Insuk Byun, Do Young Kim

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(7), P. 3253 - 3272

Published: Jan. 1, 2024

This review delineates emerging technologies for targeted protein degradation that directly involve lysosomes or proteasomes. It explores their unique features, advantages, and limitations, offering perspectives on future therapeutic applications.

Language: Английский

Citations

25
Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders DOI Creative Commons
Corentin Bouvier, Rachel Lawrence,

Francesca Cavallo

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 578 - 578

Published: March 26, 2024

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding ubiquitin ligase. More generally referred as bifunctional degraders, PROTACs have led the way in field targeted protein (TPD), with several currently undergoing clinical testing. Alongside single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered viable approach for development therapeutics, driven advances rational discovery approaches. This review focuses on drug respect within proteasome system, including analysis mechanistic concepts approaches, an overview current pre-clinical degrader status oncology, neurodegenerative inflammatory disease.

Language: Английский

Citations

7
Exploration of Degrons and Their Ability to Mediate Targeted Protein Degradation DOI
Timothy J. Harris, Darci J. Trader

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Degrons are regions of a protein that required to initiate their degradation by cellular machinery.

Language: Английский

Citations

0
Small molecule targeted protein degradation via the UPS: venturing beyond E3 substrate receptors DOI
Renyu Guo,

Fukang Yang,

Emily C. Cherney

et al.

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

As the field of targeted protein degradation has advanced, it expanded beyond traditional recruitment to E3 substrate receptors new approaches involving a variety other components within ubiquitin proteasome system.

Language: Английский

Citations

0
Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains DOI Creative Commons
Chuhui Huang, Claire L. Harris, Ghizal Siddiqui

et al.

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(4), P. 978 - 1012

Published: March 14, 2025

Thienotriazolodiazepines, including (+)-JQ1 (4), are well-known inhibitors of the bromodomain (BD) and extra-terminal domain (BET) family proteins. Despite suboptimal physicochemical properties as a drug candidate, such poor solubility half-life, (4) has proven an effective chemical probe with high target potency selectivity. (+)-JQ1-derived probes have played vital role in biology discovery over past decade, which is demonstrated by number impactful research studies published since disclosure 2010. In this review, we discuss development (+)-JQ1-derivatized decade their significant contribution to scientific research. Specifically, will summarize innovative label-free labeled probes, bivalent, covalent, photoaffinity well protein degraders, focus on design these probes.

Language: Английский

Citations

0
Primed for Interactions: Investigating the Primed Substrate Channel of the Proteasome for Improved Molecular Engagement DOI Creative Commons
Cody A. Loy, Darci J. Trader

Molecules, Journal Year: 2024, Volume and Issue: 29(14), P. 3356 - 3356

Published: July 17, 2024

Protein homeostasis is a tightly conserved process that regulated through the ubiquitin proteasome system (UPS) in ubiquitin-independent or ubiquitin-dependent manner. Over past two decades, has become an excellent therapeutic target inhibition of catalytic core particle, subunits responsible for recognizing and binding ubiquitinated proteins, more recently, targeted protein degradation using proteolysis targeting chimeras (PROTACs). The majority developed inhibitors proteasome's particle rely on gaining selectivity interactions within unprimed substrate channel. Although this allowed selective chemical probes to be generated different isoforms, much remains unknown about could harnessed primed channel increase potency selectivity. Herein, we discuss small molecules interact with pocket how their differences may give rise altered activity. Taking advantage additional allow generation improved tools perturbing monitoring

Language: Английский

Citations

3
Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins DOI
Laurence J. Seabrook, Carolina N. Franco, Cody A. Loy

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(12), P. 1566 - 1576

Published: Oct. 16, 2024

Language: Английский

Citations

3
Recruitment to the Proteasome Is Necessary but Not Sufficient for Chemically Induced, Ubiquitin-Independent Degradation of Native Proteins DOI
Madeline Balzarini, Joel Tong, Weijun Gui

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(11), P. 2323 - 2335

Published: Oct. 23, 2024

Targeted protein degradation (TPD) is a promising strategy for drug development. Most degraders function by forcing the association of target (TP) with an E3 Ubiquitin (Ub) ligase, which, in favorable cases, results polyubiquitylation TP and its subsequent 26S proteasome. An alternative would be to create chemical dimerizers that bypass requirement recruiting directly Direct-to-proteasome (DPDs) may exhibit different characteristics than ubiquitin-dependent degraders, but few studies this type TPD have been published, largely due dearth suitable proteasome ligands. To facilitate DPDs, we report here mammalian cell line which HaloTag fused via Rpn13, one ubiquitin receptors. In these cells, chloroalkane serves as covalent ligand surrogate. We show chimeric molecules comprised linked BET family proteins or Cdk2/7/9 kinases result ubiquitin-independent some proteins. use system, first allows facile native fashion, probe two issues: effect varying length linker connecting selectivity within families engaged ligand.

Language: Английский

Citations

3
DiPTAC: A degradation platform via directly targeting proteasome DOI Creative Commons

Yutong Tu,

Qian Yu, Mengna Li

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 15(1), P. 661 - 664

Published: Sept. 7, 2024

Language: Английский

Citations

1
Ubiquitin‐Independent Degradation: An Emerging PROTAC Approach? DOI Creative Commons
Tiantian Li, Saskia A. Hogenhout, Weijie Huang

et al.

BioEssays, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

ABSTRACT Targeted protein degradation (TPD) has emerged as a highly promising approach for eliminating disease‐associated proteins in the field of drug discovery. Among most advanced TPD technologies, PROteolysis TArgeting Chimera (PROTAC), functions by bringing interest (POI) into proximity with an E3 ubiquitin ligase, leading to (Ub)‐dependent proteasomal degradation. However, designs PROTACs are based on utilization limited number available ligases, which significantly restricts their potential. Recent studies have shown that phytoplasmas, group bacterial plant pathogens, developed several E3‐ and ubiquitin‐independent (UbInPD) mechanisms breaking down host targets. This suggests alternative substrate recruitment TPD. Here, we present existing evidence supports feasibility UbInPD eukaryotic cells propose candidate can serve docking sites development E3‐independent PROTACs.

Language: Английский

Citations

1