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

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)

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Abstract

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

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MDPI and ACS Style

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. https://doi.org/10.3390/ph13030034

AMA Style

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(3):34. https://doi.org/10.3390/ph13030034

Chicago/Turabian Style

Shoda, Takuji, Nobumichi Ohoka, Genichiro Tsuji, Takuma Fujisato, Hideshi Inoue, Yosuke Demizu, Mikihiko Naito, and Masaaki Kurihara. 2020. "Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety" Pharmaceuticals 13, no. 3: 34. https://doi.org/10.3390/ph13030034

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

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