A small HDM2 antagonist peptide and a USP7 inhibitor synergistically inhibit the p53-HDM2-USP7 circuit
© 2023 John Wiley & Sons Ltd..
HDM2, an E3 ubiquitin ligase, is a crucial regulator of many proliferation-related pathways. It is also one of the primary regulators of p53. USP7, a deubiquitinase, also plays a key role in the regulation of both p53 and HDM2, thus forming a small regulatory network with them. This network has emerged as an important drug target. Development of a synergistic combination targeting both proteins is desirable and important for regulating this module. We have developed a small helically constrained peptide that potently inhibited p53-HDM2 interaction and exerted anti-proliferative effects on p53+/+ cells. A combination of this peptide-when attached to cell entry and nuclear localization tags-and a USP7 inhibitor showed synergistic anti-proliferative effects against cells harboring wild-type alleles of p53. Synergistic inhibition of two important drug targets may lead to novel therapeutic strategies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:102 |
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| Enthalten in: |
Chemical biology & drug design - 102(2023), 1 vom: 27. Juli, Seite 126-136 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mukherjee, Srijata [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.06.2023 Date Revised 22.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cbdd.14255 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM356093026 |
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| 500 | |a Date Revised 22.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 John Wiley & Sons Ltd. | ||
| 520 | |a HDM2, an E3 ubiquitin ligase, is a crucial regulator of many proliferation-related pathways. It is also one of the primary regulators of p53. USP7, a deubiquitinase, also plays a key role in the regulation of both p53 and HDM2, thus forming a small regulatory network with them. This network has emerged as an important drug target. Development of a synergistic combination targeting both proteins is desirable and important for regulating this module. We have developed a small helically constrained peptide that potently inhibited p53-HDM2 interaction and exerted anti-proliferative effects on p53+/+ cells. A combination of this peptide-when attached to cell entry and nuclear localization tags-and a USP7 inhibitor showed synergistic anti-proliferative effects against cells harboring wild-type alleles of p53. Synergistic inhibition of two important drug targets may lead to novel therapeutic strategies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HDM2 | |
| 650 | 4 | |a USP7 | |
| 650 | 4 | |a inhibition | |
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| 700 | 1 | |a Saha, Gouranga |e verfasserin |4 aut | |
| 700 | 1 | |a Roy, Neeladri Sekhar |e verfasserin |4 aut | |
| 700 | 1 | |a Naiya, Gitashri |e verfasserin |4 aut | |
| 700 | 1 | |a Ghosh, Mrinal K |e verfasserin |4 aut | |
| 700 | 1 | |a Roy, Siddhartha |e verfasserin |4 aut | |
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