Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability
The von Hippel–Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic stru...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2024-06, Vol.67 (11), p.8585-8608 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 8608 |
|---|---|
| container_issue | 11 |
| container_start_page | 8585 |
| container_title | Journal of medicinal chemistry |
| container_volume | 67 |
| creator | Wu, Hao Murray, Jeremy Ishisoko, Noriko Frommlet, Alexandra Deshmukh, Gauri DiPasquale, Antonio Mulvihill, Melinda M. Zhang, Donglu Quinn, John G. Blake, Robert A. Fairbrother, Wayne J. Fuhrmann, Jakob |
| description | The von Hippel–Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic structure–activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, GNE7599, will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation. |
| doi_str_mv | 10.1021/acs.jmedchem.3c02203 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3062528872</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3062528872</sourcerecordid><originalsourceid>FETCH-LOGICAL-a297t-96460f9ea7a36b383d1148113da577693fcb4a01f4bde1d636207d35d02a17f53</originalsourceid><addsrcrecordid>eNp9kE1PwzAMhiMEYmPwDxDqkUuHk7RpewQ02KSJ7QBcIzdJWaZ-jKYd2r8nsI0jJ0v289rJQ8g1hTEFRu9QufG6MlqtTDXmChgDfkKGNGYQRilEp2QIvhkywfiAXDi3BgBOGT8nA56mkCVCDMnLsulMrXbhpF5hrYwOlmbTWd1UtjKdVcH7dB7M7QfW2gVftlsFs2rTNlsPLlosgwfb4BZtibktbbe7JGcFls5cHeqIvD1NXh-n4XzxPHu8n4fIsqQLMxEJKDKDCXKR85RrSqOUUq4xThKR8ULlEQItolwbqgUXDBLNYw0MaVLEfERu93v9Wz574zpZWadMWWJtmt5JDoLFLE0T5tFoj6q2ca41hdy0tsJ2JynIH5PSm5RHk_Jg0sduDhf63M_-Qkd1HoA98Btv-rb2H_5_5zeMo4IO</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3062528872</pqid></control><display><type>article</type><title>Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Wu, Hao ; Murray, Jeremy ; Ishisoko, Noriko ; Frommlet, Alexandra ; Deshmukh, Gauri ; DiPasquale, Antonio ; Mulvihill, Melinda M. ; Zhang, Donglu ; Quinn, John G. ; Blake, Robert A. ; Fairbrother, Wayne J. ; Fuhrmann, Jakob</creator><creatorcontrib>Wu, Hao ; Murray, Jeremy ; Ishisoko, Noriko ; Frommlet, Alexandra ; Deshmukh, Gauri ; DiPasquale, Antonio ; Mulvihill, Melinda M. ; Zhang, Donglu ; Quinn, John G. ; Blake, Robert A. ; Fairbrother, Wayne J. ; Fuhrmann, Jakob</creatorcontrib><description>The von Hippel–Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic structure–activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, GNE7599, will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c02203</identifier><identifier>PMID: 38809766</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Biological Availability ; Humans ; Ligands ; Peptidomimetics - chemistry ; Peptidomimetics - pharmacokinetics ; Peptidomimetics - pharmacology ; Structure-Activity Relationship ; Von Hippel-Lindau Tumor Suppressor Protein - chemistry ; Von Hippel-Lindau Tumor Suppressor Protein - metabolism</subject><ispartof>Journal of medicinal chemistry, 2024-06, Vol.67 (11), p.8585-8608</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a297t-96460f9ea7a36b383d1148113da577693fcb4a01f4bde1d636207d35d02a17f53</cites><orcidid>0000-0002-4664-6232 ; 0000-0003-0480-5124 ; 0000-0001-8755-7036 ; 0000-0002-0057-1204</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.3c02203$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02203$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38809766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Hao</creatorcontrib><creatorcontrib>Murray, Jeremy</creatorcontrib><creatorcontrib>Ishisoko, Noriko</creatorcontrib><creatorcontrib>Frommlet, Alexandra</creatorcontrib><creatorcontrib>Deshmukh, Gauri</creatorcontrib><creatorcontrib>DiPasquale, Antonio</creatorcontrib><creatorcontrib>Mulvihill, Melinda M.</creatorcontrib><creatorcontrib>Zhang, Donglu</creatorcontrib><creatorcontrib>Quinn, John G.</creatorcontrib><creatorcontrib>Blake, Robert A.</creatorcontrib><creatorcontrib>Fairbrother, Wayne J.</creatorcontrib><creatorcontrib>Fuhrmann, Jakob</creatorcontrib><title>Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The von Hippel–Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic structure–activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, GNE7599, will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biological Availability</subject><subject>Humans</subject><subject>Ligands</subject><subject>Peptidomimetics - chemistry</subject><subject>Peptidomimetics - pharmacokinetics</subject><subject>Peptidomimetics - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein - chemistry</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1PwzAMhiMEYmPwDxDqkUuHk7RpewQ02KSJ7QBcIzdJWaZ-jKYd2r8nsI0jJ0v289rJQ8g1hTEFRu9QufG6MlqtTDXmChgDfkKGNGYQRilEp2QIvhkywfiAXDi3BgBOGT8nA56mkCVCDMnLsulMrXbhpF5hrYwOlmbTWd1UtjKdVcH7dB7M7QfW2gVftlsFs2rTNlsPLlosgwfb4BZtibktbbe7JGcFls5cHeqIvD1NXh-n4XzxPHu8n4fIsqQLMxEJKDKDCXKR85RrSqOUUq4xThKR8ULlEQItolwbqgUXDBLNYw0MaVLEfERu93v9Wz574zpZWadMWWJtmt5JDoLFLE0T5tFoj6q2ca41hdy0tsJ2JynIH5PSm5RHk_Jg0sduDhf63M_-Qkd1HoA98Btv-rb2H_5_5zeMo4IO</recordid><startdate>20240613</startdate><enddate>20240613</enddate><creator>Wu, Hao</creator><creator>Murray, Jeremy</creator><creator>Ishisoko, Noriko</creator><creator>Frommlet, Alexandra</creator><creator>Deshmukh, Gauri</creator><creator>DiPasquale, Antonio</creator><creator>Mulvihill, Melinda M.</creator><creator>Zhang, Donglu</creator><creator>Quinn, John G.</creator><creator>Blake, Robert A.</creator><creator>Fairbrother, Wayne J.</creator><creator>Fuhrmann, Jakob</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4664-6232</orcidid><orcidid>https://orcid.org/0000-0003-0480-5124</orcidid><orcidid>https://orcid.org/0000-0001-8755-7036</orcidid><orcidid>https://orcid.org/0000-0002-0057-1204</orcidid></search><sort><creationdate>20240613</creationdate><title>Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability</title><author>Wu, Hao ; Murray, Jeremy ; Ishisoko, Noriko ; Frommlet, Alexandra ; Deshmukh, Gauri ; DiPasquale, Antonio ; Mulvihill, Melinda M. ; Zhang, Donglu ; Quinn, John G. ; Blake, Robert A. ; Fairbrother, Wayne J. ; Fuhrmann, Jakob</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a297t-96460f9ea7a36b383d1148113da577693fcb4a01f4bde1d636207d35d02a17f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biological Availability</topic><topic>Humans</topic><topic>Ligands</topic><topic>Peptidomimetics - chemistry</topic><topic>Peptidomimetics - pharmacokinetics</topic><topic>Peptidomimetics - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein - chemistry</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Hao</creatorcontrib><creatorcontrib>Murray, Jeremy</creatorcontrib><creatorcontrib>Ishisoko, Noriko</creatorcontrib><creatorcontrib>Frommlet, Alexandra</creatorcontrib><creatorcontrib>Deshmukh, Gauri</creatorcontrib><creatorcontrib>DiPasquale, Antonio</creatorcontrib><creatorcontrib>Mulvihill, Melinda M.</creatorcontrib><creatorcontrib>Zhang, Donglu</creatorcontrib><creatorcontrib>Quinn, John G.</creatorcontrib><creatorcontrib>Blake, Robert A.</creatorcontrib><creatorcontrib>Fairbrother, Wayne J.</creatorcontrib><creatorcontrib>Fuhrmann, Jakob</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Hao</au><au>Murray, Jeremy</au><au>Ishisoko, Noriko</au><au>Frommlet, Alexandra</au><au>Deshmukh, Gauri</au><au>DiPasquale, Antonio</au><au>Mulvihill, Melinda M.</au><au>Zhang, Donglu</au><au>Quinn, John G.</au><au>Blake, Robert A.</au><au>Fairbrother, Wayne J.</au><au>Fuhrmann, Jakob</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-06-13</date><risdate>2024</risdate><volume>67</volume><issue>11</issue><spage>8585</spage><epage>8608</epage><pages>8585-8608</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>The von Hippel–Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic structure–activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, GNE7599, will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38809766</pmid><doi>10.1021/acs.jmedchem.3c02203</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-4664-6232</orcidid><orcidid>https://orcid.org/0000-0003-0480-5124</orcidid><orcidid>https://orcid.org/0000-0001-8755-7036</orcidid><orcidid>https://orcid.org/0000-0002-0057-1204</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2024-06, Vol.67 (11), p.8585-8608 |
| issn | 0022-2623 1520-4804 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3062528872 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Administration, Oral Animals Biological Availability Humans Ligands Peptidomimetics - chemistry Peptidomimetics - pharmacokinetics Peptidomimetics - pharmacology Structure-Activity Relationship Von Hippel-Lindau Tumor Suppressor Protein - chemistry Von Hippel-Lindau Tumor Suppressor Protein - metabolism |
| title | Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T11%3A00%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Potency-Enhanced%20Peptidomimetic%20VHL%20Ligands%20with%20Improved%20Oral%20Bioavailability&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Wu,%20Hao&rft.date=2024-06-13&rft.volume=67&rft.issue=11&rft.spage=8585&rft.epage=8608&rft.pages=8585-8608&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.3c02203&rft_dat=%3Cproquest_cross%3E3062528872%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3062528872&rft_id=info:pmid/38809766&rfr_iscdi=true |