scholarly journals Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via in Silico Design

2021 ◽  
Author(s):  
Hidetomo Yokoo ◽  
Norihito Shibata ◽  
Akinori Endo ◽  
Takahito Ito ◽  
Yuta Yanase ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Ternary Complex ◽  
Docking Simulation ◽  
Therapeutic Agents ◽  
Promising Candidate ◽  
Selective Degradation ◽  
Prostaglandin D Synthase ◽  
Ku812 Cells ◽  
Degradation Activity

<p>Hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for the development of therapeutic agents for Duchenne muscular dystrophy (DMD) and other H-PGDS-related diseases. We have recently developed the H-PGDS degrader <b>PROTAC(H-PGDS)-1</b>, which is a chimeric molecule in which TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon [CRBN]) were conjugated to the PEG5 linker. Herein, using a docking simulation of the ternary complex of the H-PGDS degrader, H-PGDS, and CRBN, we have succeeded in developing <b>PROTAC(H-PGDS)-7, </b>a new H-PGDS degrader that does not contain a linker. <b>PROTAC(H-PGDS)-7</b> showed potent and selective degradation activity (DC<sub>50</sub> = 17.3 pM), and potent suppression of prostaglandin D<sub>2</sub> (PGD<sub>2</sub>) production in KU812 cells. Additionally, in a DMD model using <i>mdx</i>mice with cardiac hypertrophy, <b>PROTAC(H-PGDS)-7</b> showed better inhibition of inflammatory cytokines than TFC-007. <b>PROTAC(H-PGDS)-7</b> is expected to be a promising candidate for the treatment of DMD and other H-PGDS-related diseases.</p>

scholarly journals Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via in Silico Design

2021 ◽  
Author(s):  
Hidetomo Yokoo ◽  
Norihito Shibata ◽  
Akinori Endo ◽  
Takahito Ito ◽  
Yuta Yanase ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Ternary Complex ◽  
Docking Simulation ◽  
Therapeutic Agents ◽  
Promising Candidate ◽  
Selective Degradation ◽  
Prostaglandin D Synthase ◽  
Ku812 Cells ◽  
Degradation Activity

<p>Hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for the development of therapeutic agents for Duchenne muscular dystrophy (DMD) and other H-PGDS-related diseases. We have recently developed the H-PGDS degrader <b>PROTAC(H-PGDS)-1</b>, which is a chimeric molecule in which TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon [CRBN]) were conjugated to the PEG5 linker. Herein, using a docking simulation of the ternary complex of the H-PGDS degrader, H-PGDS, and CRBN, we have succeeded in developing <b>PROTAC(H-PGDS)-7, </b>a new H-PGDS degrader that does not contain a linker. <b>PROTAC(H-PGDS)-7</b> showed potent and selective degradation activity (DC<sub>50</sub> = 17.3 pM), and potent suppression of prostaglandin D<sub>2</sub> (PGD<sub>2</sub>) production in KU812 cells. Additionally, in a DMD model using <i>mdx</i>mice with cardiac hypertrophy, <b>PROTAC(H-PGDS)-7</b> showed better inhibition of inflammatory cytokines than TFC-007. <b>PROTAC(H-PGDS)-7</b> is expected to be a promising candidate for the treatment of DMD and other H-PGDS-related diseases.</p>

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.

Growth and psychomotor development of patients with Duchenne Muscular Dystrophy

2012 ◽  
Vol 43 (02) ◽  
Author(s):  
E Sarrazin ◽  
M von der Hagen ◽  
U Schara ◽  
K von Au ◽  
A Kaindl
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Psychomotor Development
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