Novel quinazolin-4(3H)-one based Cyclin K degraders regulate alternative polyadenylation activity
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
Phenotypic screening is gaining attention as a powerful method for identifying compounds that regulate cellular phenotypes of interest through novel mechanisms of action. Recently, a new modality of compounds, called molecular glues, which can induce the degradation of target proteins by forming ternary complexes of E3 ligases, has emerged from phenotypic screening. In this study, using global proteomic analysis, we identified a novel Cyclin K degrader, T4, which was previously discovered through phenotypic screening for alternative polyadenylation regulation. Our detailed mechanistic analysis revealed that T4 induced Cyclin K degradation, leading to the regulation of alternative polyadenylation. Additionally, we generated a more potent Cyclin K degrader, TR-213, through a structure-activity relationship study of T4. T4 and TR-213 are structurally distinct from other Cyclin K degraders and can be used as novel chemical tools to further analyze the degradation of Cyclin K and the regulation of alternative polyadenylation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:676 |
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| Enthalten in: |
Biochemical and biophysical research communications - 676(2023) vom: 08. Okt., Seite 6-12 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sano, Osamu [VerfasserIn] |
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| Links: |
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| Themen: |
Alternative polyadenylation |
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| Anmerkungen: |
Date Completed 04.09.2023 Date Revised 04.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbrc.2023.07.028 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359809413 |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Phenotypic screening is gaining attention as a powerful method for identifying compounds that regulate cellular phenotypes of interest through novel mechanisms of action. Recently, a new modality of compounds, called molecular glues, which can induce the degradation of target proteins by forming ternary complexes of E3 ligases, has emerged from phenotypic screening. In this study, using global proteomic analysis, we identified a novel Cyclin K degrader, T4, which was previously discovered through phenotypic screening for alternative polyadenylation regulation. Our detailed mechanistic analysis revealed that T4 induced Cyclin K degradation, leading to the regulation of alternative polyadenylation. Additionally, we generated a more potent Cyclin K degrader, TR-213, through a structure-activity relationship study of T4. T4 and TR-213 are structurally distinct from other Cyclin K degraders and can be used as novel chemical tools to further analyze the degradation of Cyclin K and the regulation of alternative polyadenylation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Alternative polyadenylation | |
| 650 | 4 | |a Cyclin K | |
| 650 | 4 | |a Molecular glue | |
| 650 | 4 | |a Protein degrader | |
| 650 | 4 | |a T4 | |
| 650 | 4 | |a TR-213 | |
| 650 | 7 | |a Cyclins |2 NLM | |
| 700 | 1 | |a Ito, Masahiro |e verfasserin |4 aut | |
| 700 | 1 | |a Saito, Masayo |e verfasserin |4 aut | |
| 700 | 1 | |a Toita, Akinori |e verfasserin |4 aut | |
| 700 | 1 | |a Tanaka, Toshio |e verfasserin |4 aut | |
| 700 | 1 | |a Maezaki, Hironobu |e verfasserin |4 aut | |
| 700 | 1 | |a Araki, Shinsuke |e verfasserin |4 aut | |
| 700 | 1 | |a Iwata, Hidehisa |e verfasserin |4 aut | |
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