دورية أكاديمية
A small-molecule degron with a phenylpropionic acid scaffold.
| العنوان: | A small-molecule degron with a phenylpropionic acid scaffold. |
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| المؤلفون: | Tomoshige S; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan. Electronic address: stomohi@tohoku.ac.jp., Komatsu F; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan., Kikuchi T; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan., Sugiyama M; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan., Kawasaki Y; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan., Ohgane K; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Department of Chemistry, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan., Furuyama Y; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan., Sato S; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan; Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Aramaki aza Aoba 6-3, Aoba-ku, Sendai 980-8578, Japan., Ishikawa M; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan., Kuramochi K; Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. |
| المصدر: | Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Jul 15; Vol. 109, pp. 117789. Date of Electronic Publication: 2024 Jun 05. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Original Publication: Oxford : New York : Pergamon Press, c1993- |
| مواضيع طبية MeSH: | S-Phase Kinase-Associated Proteins*/metabolism , S-Phase Kinase-Associated Proteins*/antagonists & inhibitors , Small Molecule Libraries*/chemistry , Small Molecule Libraries*/pharmacology , Small Molecule Libraries*/chemical synthesis, Humans ; Proteolysis/drug effects ; Phenylpropionates/chemistry ; Phenylpropionates/pharmacology ; Structure-Activity Relationship ; Proteasome Endopeptidase Complex/metabolism ; Molecular Structure ; Ligands ; HEK293 Cells ; Degrons |
| مستخلص: | Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to redirect the ubiquitin-proteasome system (UPS) to the target protein, has emerged as a promising strategy in drug discovery. However, despite the vast number of E3 ligases, the repertoire of E3 ligands utilized in PROTACs remains limited. Here, we report the discovery of a small-molecule degron with a phenylpropionic acid skeleton, derived from a known ligand of S-phase kinase-interacting protein 2 (Skp2), an E3 ligase. We used this degron to design PROTACs inducing proteasomal degradation of HaloTag-fused proteins, and identified key structural relationships. Surprisingly, our mechanistic studies excluded the involvement of Skp2, suggesting that this degron recruits other protein(s) within the UPS. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Phenylpropionic acid; Small-molecule degron; Targeted protein degradation |
| المشرفين على المادة: | 0 (S-Phase Kinase-Associated Proteins) 0 (Small Molecule Libraries) 0 (Phenylpropionates) EC 3.4.25.1 (Proteasome Endopeptidase Complex) 0 (SKP2 protein, human) 0 (Ligands) |
| تواريخ الأحداث: | Date Created: 20240613 Date Completed: 20240628 Latest Revision: 20240628 |
| رمز التحديث: | 20240629 |
| DOI: | 10.1016/j.bmc.2024.117789 |
| PMID: | 38870716 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1464-3391 |
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| DOI: | 10.1016/j.bmc.2024.117789 |