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 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.

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 Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

Discovery of small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy

2017 ◽  
Vol 27 ◽  
pp. S189
Author(s):  
G. Wynne ◽  
A. Vuorinen ◽  
E. Emer ◽  
D. Conole ◽  
M. Chatzopoulou ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Small Molecule

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 A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy

2020 ◽  
Author(s):  
Gist H. Farr ◽  
Melanie Morris ◽  
Arianna Gomez ◽  
Thao Pham ◽  
Elizabeth U. Parker ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Small Molecules ◽  
Small Molecule ◽  
Histone Deacetylase Inhibitors ◽  
Neuromuscular Disorder ◽  
Small Molecule Screen ◽  
Chemical Screen ◽  
Novel Drug

SummaryDuchenne muscular dystrophy (DMD) is a severe neuromuscular disorder and is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although many small-molecule approaches are being pursued. Specific histone deacetylase inhibitors (HDACi) can ameliorate DMD phenotypes in mouse and zebrafish animal models and have also shown promise for DMD in clinical trials. However, beyond these HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Here, we performed a novel chemical screen of a library of epigenetic compounds using the zebrafish dmd model. We identified candidate pools of epigenetic compounds that improve skeletal muscle structure in dmd zebrafish. We then identified a specific combination of two drugs, oxamflatin and salermide, that significantly rescued dmd zebrafish skeletal muscle degeneration. Furthermore, we validated the effects of oxamflatin and salermide in an independent laboratory. Our results provide novel, effective methods for performing a combination small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.

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