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Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety

1
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
2
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa 210-9501, Japan
3
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Current address: School of Pharmacy, Department of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara, Tochigi, Japan.
Pharmaceuticals 2020, 13(3), 34; https://doi.org/10.3390/ph13030034
Received: 20 January 2020 / Revised: 19 February 2020 / Accepted: 19 February 2020 / Published: 25 February 2020
(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)
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, 2, 3, and 16 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, 2, 3, and 16 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. View Full-Text
Keywords: protein degradation; chimeric compound; hydrophobic tagging; adamantane protein degradation; chimeric compound; hydrophobic tagging; adamantane
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Shoda, T.; Ohoka, N.; Tsuji, G.; Fujisato, T.; Inoue, H.; Demizu, Y.; Naito, M.; Kurihara, M. Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety. Pharmaceuticals 2020, 13, 34.

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