Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety
Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/13/3/34 |
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| author | Takuji Shoda Nobumichi Ohoka Genichiro Tsuji Takuma Fujisato Hideshi Inoue Yosuke Demizu Mikihiko Naito Masaaki Kurihara |
| author_facet | Takuji Shoda Nobumichi Ohoka Genichiro Tsuji Takuma Fujisato Hideshi Inoue Yosuke Demizu Mikihiko Naito Masaaki Kurihara |
| author_sort | Takuji Shoda |
| collection | DOAJ |
| description | Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, <b>2</b>, <b>3</b>, and <b>16</b> induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, <b>2</b>, <b>3</b>, and <b>16</b> did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR. |
| first_indexed | 2024-12-12T03:52:11Z |
| format | Article |
| id | doaj.art-eea8d0eaf35a447d86d0789256ee0c02 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-12-12T03:52:11Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-eea8d0eaf35a447d86d0789256ee0c022022-12-22T00:39:22ZengMDPI AGPharmaceuticals1424-82472020-02-011333410.3390/ph13030034ph13030034Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane MoietyTakuji Shoda0Nobumichi Ohoka1Genichiro Tsuji2Takuma Fujisato3Hideshi Inoue4Yosuke Demizu5Mikihiko Naito6Masaaki Kurihara7Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanDivision of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanSchool of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanDivision of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanDivision of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, JapanTargeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, <b>2</b>, <b>3</b>, and <b>16</b> induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, <b>2</b>, <b>3</b>, and <b>16</b> did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR.https://www.mdpi.com/1424-8247/13/3/34protein degradationchimeric compoundhydrophobic taggingadamantane |
| spellingShingle | Takuji Shoda Nobumichi Ohoka Genichiro Tsuji Takuma Fujisato Hideshi Inoue Yosuke Demizu Mikihiko Naito Masaaki Kurihara Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety Pharmaceuticals protein degradation chimeric compound hydrophobic tagging adamantane |
| title | Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety |
| title_full | Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety |
| title_fullStr | Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety |
| title_full_unstemmed | Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety |
| title_short | Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety |
| title_sort | targeted protein degradation by chimeric compounds using hydrophobic e3 ligands and adamantane moiety |
| topic | protein degradation chimeric compound hydrophobic tagging adamantane |
| url | https://www.mdpi.com/1424-8247/13/3/34 |
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