Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening
Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold target...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/106844 |
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| _version_ | 1849335437027442688 |
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| author | Han Zhou Tonglian Zhou Wenli Yu Liping Liu Yeonjin Ko Kristen A Johnson Ian A Wilson Peter G Schultz Michael J Bollong |
| author_facet | Han Zhou Tonglian Zhou Wenli Yu Liping Liu Yeonjin Ko Kristen A Johnson Ian A Wilson Peter G Schultz Michael J Bollong |
| author_sort | Han Zhou |
| collection | DOAJ |
| description | Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening. |
| format | Article |
| id | doaj-art-adffac5b7d8b4036a17ab14a91fc110c |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-adffac5b7d8b4036a17ab14a91fc110c2025-08-20T03:45:15ZengeLife Sciences Publications LtdeLife2050-084X2025-06-011410.7554/eLife.106844Targeted protein degradation by KLHDC2 ligands identified by high-throughput screeningHan Zhou0Tonglian Zhou1Wenli Yu2Liping Liu3Yeonjin Ko4Kristen A Johnson5Ian A Wilson6Peter G Schultz7Michael J Bollong8https://orcid.org/0000-0001-9439-1476Department of Chemistry, Scripps Research, La Jolla, United StatesDepartment of Chemistry, Scripps Research, La Jolla, United StatesDepartment of Integrative Structural and Computational Biology, Scripps Research, La Jolla, United StatesDepartment of Chemistry, Scripps Research, La Jolla, United StatesChemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaDepartment of Biology, Calibr-Skaggs at Scripps Research, La Jolla, United StatesDepartment of Integrative Structural and Computational Biology, Scripps Research, La Jolla, United StatesDepartment of Chemistry, Scripps Research, La Jolla, United StatesDepartment of Chemistry, Scripps Research, La Jolla, United StatesProteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening.https://elifesciences.org/articles/106844KLHDC2PROTACE3 ligasehigh-throughput screening |
| spellingShingle | Han Zhou Tonglian Zhou Wenli Yu Liping Liu Yeonjin Ko Kristen A Johnson Ian A Wilson Peter G Schultz Michael J Bollong Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening eLife KLHDC2 PROTAC E3 ligase high-throughput screening |
| title | Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening |
| title_full | Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening |
| title_fullStr | Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening |
| title_full_unstemmed | Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening |
| title_short | Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening |
| title_sort | targeted protein degradation by klhdc2 ligands identified by high throughput screening |
| topic | KLHDC2 PROTAC E3 ligase high-throughput screening |
| url | https://elifesciences.org/articles/106844 |
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