Progress on small-molecule proteolysis-targeting chimeras

2019 ◽  
Vol 11 (20) ◽  
pp. 2715-2734 ◽  
Author(s):  
Wenhai Huang ◽  
Beibei Wang ◽  
Zhimin Zhang ◽  
Chixiao Zhang ◽  
Shenxin Zeng ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Intervention ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Target Protein ◽  
Research Progress ◽  
Target Proteins ◽  
Ubiquitin Proteasome

Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin–proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.

Small-molecule PROTACs: novel agents for cancer therapy

2020 ◽  
Vol 12 (10) ◽  
pp. 915-938
Author(s):  
Yichao Wan ◽  
Chunxing Yan ◽  
Han Gao ◽  
Tingting Liu
Keyword(s):  
Drug Resistance ◽  
Cancer Therapy ◽  
Small Molecule ◽  
New Technology ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Novel Agents ◽  
E3 Ligases ◽  
Target Proteins ◽  
Ubiquitin Proteasome

Proteolysis-targeting chimera (PROTAC) is a new technology to selectively degrade target proteins via ubiquitin-proteasome system. PROTAC molecules (PROTACs) are a class of heterobifunctional molecules, which contain a ligand targeting the protein of interest, a ligand recruiting an E3 ligase and a linker connecting these two ligands. They provide several advantages over traditional inhibitors in potency, selectivity and drug resistance. Thus, many promising PROTACs have been developed in the recent two decades, especially small-molecule PROTACs. In this review, we briefly introduce the mechanism of PROTACs and focus on the progress of small-molecule PROTACs based on different E3 ligases. In addition, we also introduce the opportunities and challenges of small-molecule PROTACs for cancer therapy.

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.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

scholarly journals Old players in new posts: the role of P53, ATM and DNAPK in DNA damage-related ubiquitylation-dependent removal of S2P RNAPII

2021 ◽  
Author(s):  
Barbara N Borsos ◽  
Vasiliki Pantazi ◽  
Zoltán G Páhi ◽  
Hajnalka Majoros ◽  
Zsuzsanna Ujfaludi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase Ii ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Dna Double Strand Breaks ◽  
Damage Site ◽  
Strand Breaks ◽  
Cullin 3 ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

AbstractDNA double-strand breaks are the most deleterious lesions for the cells, therefore understanding the macromolecular interactions in the DNA repair-related mechanisms is essential. DNA damage triggers transcription silencing at the damage site, leading to the removal of the elongating RNA polymerase II (S2P RNAPII) from this locus, which provides accessibility for the repair factors to the lesion. Ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNAPK) are the two main regulatory kinases of homologous recombination and non-homologous end joining, respectively. Although these kinases are involved in the activation of different repair pathways, they have common target proteins, such as P53. We previously demonstrated that following transcription block, P53 plays a pivotal role in transcription elongation process by interacting with S2P RNAPII. In the current study, we reveal that P53, ATM and DNAPK are involved in the fine-tune regulation of the ubiquitin-proteasome system-related degradation of S2P RNAPII. However, they act differently in this process: P53 delays the removal of S2P RNAPII, while ATM and DNAPK participate in the activation of members of E3 ligase complexes involved in the ubiquitylation of S2P RNAPII. We also demonstrate that WW domain-containing protein 2 (WWP2) and Cullin-3 (CUL3) are interaction partners of S2P RNAPII, thus forming a complex with the transcribing RNAPII complex.Simple SummaryTo ensure the proper repair following DNA double-strand breaks, the eviction of the arrested elongating RNA polymerase II (S2P RNAPII) is required. Here, we report an emerging role of P53, Ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNAPK) in the ubiquitin-proteasome system-dependent removal of S2P RNAPII. We also identified interactions between S2P RNAPII and WW domain-containing protein 2 (WWP2) or Cullin-3 (CUL3) (members of E3 ligase complexes), which are involved in the ubiquitylation of S2P RNAPII following DNA damage. Furthermore, the RNAPII-E3 ligase complex interactions are mediated by P53, ATM and DNAPK, which suggests potential participation of all three proteins in the effective resolution of transcription block at the damage site. Altogether, our results provide a better comprehension of the molecular background of transcription elongation block-related DNA repair processes and highlight an indispensable function of P53, ATM and DNAPK in these mechanisms.

scholarly journals Rotavirus NSP1 Associates with Components of the Cullin RING Ligase Family of E3 Ubiquitin Ligases

2016 ◽  
Vol 90 (13) ◽  
pp. 6036-6048 ◽  
Author(s):  
Lindy M. Lutz ◽  
Chandler R. Pace ◽  
Michelle M. Arnold
Keyword(s):  
Mass Spectrometry ◽  
Ubiquitin Ligase ◽  
Nonstructural Protein ◽  
Ubiquitin Proteasome System ◽  
Scaffolding Proteins ◽  
Target Proteins ◽  
Rotavirus A ◽  
Ubiquitin Proteasome ◽  
Infected Cells

ABSTRACTThe rotavirus nonstructural protein NSP1 acts as an antagonist of the host antiviral response by inducing degradation of key proteins required to activate interferon (IFN) production. Protein degradation induced by NSP1 is dependent on the proteasome, and the presence of a RING domain near the N terminus has led to the hypothesis that NSP1 is an E3 ubiquitin ligase. To examine this hypothesis, pulldown assays were performed, followed by mass spectrometry to identify components of the host ubiquitination machinery that associate with NSP1. Multiple components of cullin RING ligases (CRLs), which are essential multisubunit ubiquitination complexes, were identified in association with NSP1. The mass spectrometry was validated in both transfected and infected cells to show that the NSP1 proteins from different strains of rotavirus associated with key components of CRL complexes, most notably the cullin scaffolding proteins Cul3 and Cul1.In vitrobinding assays using purified proteins confirmed that NSP1 specifically interacted with Cul3 and that the N-terminal region of Cul3 was responsible for binding to NSP1. To test if NSP1 used CRL3 to induce degradation of the target protein IRF3 or β-TrCP, Cul3 levels were knocked down using a small interfering RNA (siRNA) approach. Unexpectedly, loss of Cul3 did not rescue IRF3 or β-TrCP from degradation in infected cells. The results indicate that, rather than actively using CRL complexes to induce degradation of target proteins required for IFN production, NSP1 may use cullin-containing complexes to prevent another cellular activity.IMPORTANCEThe ubiquitin-proteasome pathway plays an important regulatory role in numerous cellular functions, and many viruses have evolved mechanisms to exploit or manipulate this pathway to enhance replication and spread. Rotavirus, a major cause of severe gastroenteritis in young children that causes approximately 420,000 deaths worldwide each year, utilizes the ubiquitin-proteasome system to subvert the host innate immune response by inducing the degradation of key components required for the production of interferon (IFN). Here, we show that NSP1 proteins from different rotavirus strains associate with the scaffolding proteins Cul1 and Cul3 of CRL ubiquitin ligase complexes. Nonetheless, knockdown of Cul1 and Cul3 suggests that NSP1 induces the degradation of some target proteins independently of its association with CRL complexes, stressing a need to further investigate the mechanistic details of how NSP1 subverts the host IFN response.

scholarly journals Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

2020 ◽  
Author(s):  
Hidetomo Yokoo ◽  
Norihito Shibata ◽  
Miyako Naganuma ◽  
Kiyonaga Fujii ◽  
Takahito Ito ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Small Molecule ◽  
Allergic Diseases ◽  
Ubiquitin Proteasome System ◽  
Novel Agents ◽  
Biological Research ◽  
Prostaglandin D2 ◽  
Prostaglandin D Synthase ◽  
Ubiquitin Proteasome

Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other mode of actions to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, PROTAC(H-PGDS)-1, was developed. PROTAC(H-PGDS)-1 is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). PROTAC(H-PGDS)-1 showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D2 (PGD2) production. Notably, PROTAC(H-PGDS)-1 was slightly more effective in the suppression of PGD2 production than the known inhibitor, TFC-007. Thus, the H-PGDS degrader—PROTAC(H-PGDS)-1—is expected to be useful in biological research and clinical therapies.

scholarly journals Predator: A novel method for targeted protein degradation

2020 ◽  
Author(s):  
Chuanyang Liu ◽  
Jingyu Kuang ◽  
Xinyuan Qiu ◽  
Lu Min ◽  
Wenying Li ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Protein Expression ◽  
Protein Degradation ◽  
E3 Ligase ◽  
Target Protein ◽  
Receptor Interaction ◽  
Physiological Status ◽  
Ubiquitin Proteasome ◽  
Bifunctional Fusion Protein ◽  
Predator System

AbstractProtein expression and degradation are fundamental to cell function and physiological status of organisms. Interfering with protein expression not only provides powerful strategies to analyze the function of proteins but also inspires effective treatment methods for diseases caused by protein dysfunction. Recently, harnessing the power of the ubiquitin-proteasome system for targeted protein degradation (TPD) has become the focus of researches. Over the past two decades, TPD technologies, such as E3 ligase modification, PROTACs, and the Trim-Away method, have successfully re-oriented the ubiquitin-proteasome pathway and thus degraded many pathogenic proteins and even "undruggable" targets. However, A low-cost, convenient, and modularized TPD method is currently not available. Herein, we proposed a synthetic biology TPD method, termed Predator, by integrating the classic function of E3 ligase Trim21 and the expression of a bifunctional fusion protein that links Trim21 and the target protein, which leads to the formation of a ternary complex inside mammalian cells and therefore induce the ubiquitination and subsequent proteasome-dependent degradation of the target protein. We first proved this concept by using nanobody and scFv as the targeting module for the Predator system to degrade free GFP and membrane protein ErbB3, respectively. Then, we give an example of how the engineered Predator system can be developed towards biomedical solutions in the context of diabetes mellitus. Ligands-receptor interaction and adenovirus-mediated gene delivery were introduced to the Predator system, and we found this bifunctional fusion protein, in which glucagon was selected to function as the targeting module, downregulated the endogenous glucagon receptor (GCGR) and attenuated glucagon-stimulated glucose production in primary hepatocytes. Although preliminarily, our results showed that this Predator system is a highly modularized and convenient TPD method with good potential for both fundamental researches and clinical usage.Graphic abstract

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