scholarly journals Patented small molecule inhibitors in the ubiquitin proteasome system

2007 ◽  
Vol 8 (Suppl 1) ◽  
pp. S14 ◽  
Author(s):  
Philippe Guédat ◽  
Frédéric Colland
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3079
Author(s):  
Gabriel LaPlante ◽  
Wei Zhang
Keyword(s):  
Protein Degradation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Proteasome Inhibitors ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
E3 Ligases ◽  
Protein Levels ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

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.

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.

Recent advances in small molecule PROTACs for the treatment of cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Wen Li ◽  
Reham M. Elhassan ◽  
Xuben Hou ◽  
Hao Fang
Keyword(s):  
Clinical Trial ◽  
Drug Resistance ◽  
Cancer Therapy ◽  
Phase I ◽  
Small Molecule ◽  
Ubiquitin Proteasome System ◽  
Targeted Cancer Therapy ◽  
Recent Advances ◽  
Ubiquitin Proteasome ◽  
The Ideal

: The PROTAC (PROteolysis TArgeting Chimera) technology is a target protein degradation strategy, based on the ubiquitin-proteasome system, which has been gradually developed into a potential means of targeted cancer therapy in recent years. This strategy has already shown significant advantages over traditional small-molecule inhibitors in terms of pharmacodynamics, selectivity, and drug resistance. Several small molecule PROTACs have been in a Phase I clinical trial. Herein, we introduced the mechanism, characteristics, and advantages of PROTAC strategy. And we summarize the recent advances in the development of small-molecule PROTACs for cancer treatment. We hope this review will be helpful in optimizing the design of the ideal small-molecule PROTACs and advancing targeted anticancer research.

scholarly journals Methods to Discover and Evaluate Proteasome Small Molecule Stimulators

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2341 ◽  
Author(s):  
Rachel A. Coleman ◽  
Darci J. Trader
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Small Molecule ◽  
Protease Activity ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Protein Accumulation ◽  
Toxic Protein ◽  
Disease States ◽  
Ubiquitin Proteasome

Protein accumulation has been identified as a characteristic of many degenerative conditions, such as neurodegenerative diseases and aging. In most cases, these conditions also present with diminished protein degradation. The ubiquitin-proteasome system (UPS) is responsible for the degradation of the majority of proteins in cells; however, the activity of the proteasome is reduced in these disease states, contributing to the accumulation of toxic protein. It has been hypothesized that proteasome activity, both ubiquitin-dependent and -independent, can be chemically stimulated to reduce the load of protein in diseased cells. Several methods exist to identify and characterize stimulators of proteasome activity. In this review, we detail the ways in which protease activity can be enhanced and analyze the biochemical and cellular methods of identifying stimulators of both the ubiquitin-dependent and -independent proteasome activities.

scholarly journals Identification and Mechanistic Studies of a Novel Ubiquitin E1 Inhibitor

2012 ◽  
Vol 17 (4) ◽  
pp. 421-434 ◽  
Author(s):  
Dana Ungermannova ◽  
Seth J. Parker ◽  
Christopher G. Nasveschuk ◽  
Douglas A. Chapnick ◽  
Andrew J. Phillips ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Small Molecule Compound ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway

Protein degradation via the ubiquitin-proteasome pathway is important for a diverse number of cellular processes ranging from cell signaling to development. Disruption of the ubiquitin pathway occurs in a variety of human diseases, including several cancers and neurological disorders. Excessive proteolysis of tumor suppressor proteins, such as p27, occurs in numerous aggressive human tumors. To discover small-molecule inhibitors that potentially prevent p27 degradation, we developed a series of screening assays, including a cell-based screen of a small-molecule compound library and two novel nucleotide exchange assays. Several small-molecule inhibitors, including NSC624206, were identified and subsequently verified to prevent p27 ubiquitination in vitro. The mechanism of NSC624206 inhibition of p27 ubiquitination was further unraveled using the nucleotide exchange assays and shown to be due to antagonizing ubiquitin activating enzyme (E1). We determined that NSC624206 and PYR-41, a recently reported inhibitor of ubiquitin E1, specifically block ubiquitin-thioester formation but have no effect on ubiquitin adenylation. These studies reveal a novel E1 inhibitor that targets a specific step of the E1 activation reaction. NSC624206 could, therefore, be potentially useful for the control of excessive ubiquitin-mediated proteolysis in vivo.

Abstract LB-049: Targeting the ubiquitin-proteasome system by small molecule inhibition of the DUBome

2019 ◽  
Author(s):  
Tim Harrison ◽  
Xavier Jacq ◽  
Colin O'Dowd ◽  
Gerald Gavory ◽  
Oliver Barker ◽  
...  
Keyword(s):  
Small Molecule ◽  
Ubiquitin Proteasome System ◽  
Small Molecule Inhibition ◽  
Ubiquitin Proteasome

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.

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