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

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.

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Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

10.26434/chemrxiv.13040723.v1 ◽

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.

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

10.1101/2020.02.19.956532 ◽

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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Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

International Journal of Molecular Sciences ◽

10.3390/ijms20174098 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4098 ◽

Cited By ~ 23

Author(s):

Tatyana A. Meyers ◽

DeWayne Townsend

Keyword(s):

Heart Disease ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Small Molecule ◽

Genetic Defect ◽

Dystrophin Gene ◽

Gene Replacement ◽

Therapeutic Approaches ◽

Respiratory Management ◽

Dystrophic Cardiomyopathy

Duchenne muscular dystrophy (DMD) is a devastating disease featuring skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. Historically, respiratory failure has been the leading cause of mortality in DMD, but recent improvements in symptomatic respiratory management have extended the life expectancy of DMD patients. With increased longevity, the clinical relevance of heart disease in DMD is growing, as virtually all DMD patients over 18 year of age display signs of cardiomyopathy. This review will focus on the pathophysiological basis of DMD in the heart and discuss the therapeutic approaches currently in use and those in development to treat dystrophic cardiomyopathy. The first section will describe the aspects of the DMD that result in the loss of cardiac tissue and accumulation of fibrosis. The second section will discuss cardiac small molecule therapies currently used to treat heart disease in DMD, with a focus on the evidence supporting the use of each drug in dystrophic patients. The final section will outline the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, or repair. There are several new and promising therapeutic approaches that may protect the dystrophic heart, but their limitations suggest that future management of dystrophic cardiomyopathy may benefit from combining gene-targeted therapies with small molecule therapies. Understanding the mechanistic basis of dystrophic heart disease and the effects of current and emerging therapies will be critical for their success in the treatment of patients with DMD.

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A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy

Skeletal Muscle ◽

10.1186/s13395-020-00251-4 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Gist H. Farr ◽

Melanie Morris ◽

Arianna Gomez ◽

Thao Pham ◽

Elisabeth Kilroy ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Small Molecules ◽

Small Molecule ◽

Histone Deacetylase Inhibitors ◽

Neuromuscular Disorder ◽

Muscle Structure ◽

Histone H4 Acetylation ◽

Chemical Combination

Abstract Background Duchenne 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. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models. The HDACi givinostat has shown promise for DMD in clinical trials. However, beyond a small group of HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Methods We used an established animal model for DMD, the zebrafish dmd mutant strain sapje. A commercially available library of epigenetic small molecules was used to treat embryonic-larval stages of dmd mutant zebrafish. We used a quantitative muscle birefringence assay in order to assess and compare the effects of small-molecule treatments on dmd mutant zebrafish skeletal muscle structure. Results We performed a novel chemical-combination 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 mutant zebrafish. We then identified a specific combination of two HDACi compounds, oxamflatin and salermide, that ameliorated dmd mutant zebrafish skeletal muscle degeneration. We validated the effects of oxamflatin and salermide on dmd mutant zebrafish in an independent laboratory. Furthermore, we showed that the combination of oxamflatin and salermide caused increased levels of histone H4 acetylation in zebrafish larvae. Conclusions Our results provide novel, effective methods for performing a combination of 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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