Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2
Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrysta...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2023-07, Vol.66 (14), p.9916-9933 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 9933 |
|---|---|
| container_issue | 14 |
| container_start_page | 9916 |
| container_title | Journal of medicinal chemistry |
| container_volume | 66 |
| creator | Huber, Max E. Wurnig, Silas Toy, Lara Weiler, Corinna Merten, Nicole Kostenis, Evi Hansen, Finn K. Schiedel, Matthias |
| description | Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (1), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 (9a) as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner. Further, we show that 9a can be used as a tool to visualize intracellular target engagement for CXCR2 via fluorescence microscopy. Thus, our small-molecule-based fluorescent CXCR2 ligand 9a represents a promising tool for future studies of CXCR2 pharmacology. |
| doi_str_mv | 10.1021/acs.jmedchem.3c00769 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10388362</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2839739387</sourcerecordid><originalsourceid>FETCH-LOGICAL-a450t-faced7b6f997cdf4b0247c59a39b09c83386dcadeb0532ee926d4d8ab09eed563</originalsourceid><addsrcrecordid>eNp9UU1v1DAUtBCILlv-AUI-csnWsfPlEypRC5VWQuqHxM1y7JesS2IvtlOJK78cp7utyoWTZb2ZefNmEPqQk01OaH4mVdjcT6DVDqYNU4TUFX-FVnlJSVY0pHiNVoRQmtGKshP0LoR7QgjLKXuLTlhdVKzg1Qr9uRxn5yEosBFvzSCtDvjCym4EfCv9ADH9BjnAtABu4qwNBNw7j-MO8JWNXioYx3mUHp-PowsRvFH4i7Ha2AHfmAjY9Y_gNhl1P40FfA0K9jFptD_aa3qK3vRyDPD--K7R3eXFbfst237_etWebzNZlCRmfVqk667qOa-V7ouO0KJWJZeMd4SrhrGm0kpq6EjJKACnlS50I9MQQJcVW6PPB9393C25wWJ-FHtvJul_CyeN-HdizU4M7kHkhDUNSzGu0aejgne_ZghRTCYs50sLbg6CNozXjLOmTtDiAFXeheChf96TE7H0J1J_4qk_cewv0T6-9PhMeiosAcgB8Eh3s7cpsv9r_gX0Kq4M</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2839739387</pqid></control><display><type>article</type><title>Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Huber, Max E. ; Wurnig, Silas ; Toy, Lara ; Weiler, Corinna ; Merten, Nicole ; Kostenis, Evi ; Hansen, Finn K. ; Schiedel, Matthias</creator><creatorcontrib>Huber, Max E. ; Wurnig, Silas ; Toy, Lara ; Weiler, Corinna ; Merten, Nicole ; Kostenis, Evi ; Hansen, Finn K. ; Schiedel, Matthias</creatorcontrib><description>Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (1), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 (9a) as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner. Further, we show that 9a can be used as a tool to visualize intracellular target engagement for CXCR2 via fluorescence microscopy. Thus, our small-molecule-based fluorescent CXCR2 ligand 9a represents a promising tool for future studies of CXCR2 pharmacology.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c00769</identifier><identifier>PMID: 37463496</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Allosteric Site ; Ligands ; Protein Binding ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Interleukin-8B</subject><ispartof>Journal of medicinal chemistry, 2023-07, Vol.66 (14), p.9916-9933</ispartof><rights>2023 The Authors. Published by American Chemical Society</rights><rights>2023 The Authors. Published by American Chemical Society 2023 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a450t-faced7b6f997cdf4b0247c59a39b09c83386dcadeb0532ee926d4d8ab09eed563</citedby><cites>FETCH-LOGICAL-a450t-faced7b6f997cdf4b0247c59a39b09c83386dcadeb0532ee926d4d8ab09eed563</cites><orcidid>0000-0001-8284-5514 ; 0000-0001-6932-2217 ; 0000-0001-7365-3617 ; 0009-0009-6708-7415 ; 0009-0006-7809-1426 ; 0000-0002-8487-6805 ; 0000-0003-3042-0463 ; 0000-0001-9765-5975</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.3c00769$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00769$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37463496$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huber, Max E.</creatorcontrib><creatorcontrib>Wurnig, Silas</creatorcontrib><creatorcontrib>Toy, Lara</creatorcontrib><creatorcontrib>Weiler, Corinna</creatorcontrib><creatorcontrib>Merten, Nicole</creatorcontrib><creatorcontrib>Kostenis, Evi</creatorcontrib><creatorcontrib>Hansen, Finn K.</creatorcontrib><creatorcontrib>Schiedel, Matthias</creatorcontrib><title>Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (1), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 (9a) as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner. Further, we show that 9a can be used as a tool to visualize intracellular target engagement for CXCR2 via fluorescence microscopy. Thus, our small-molecule-based fluorescent CXCR2 ligand 9a represents a promising tool for future studies of CXCR2 pharmacology.</description><subject>Allosteric Site</subject><subject>Ligands</subject><subject>Protein Binding</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Interleukin-8B</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAUtBCILlv-AUI-csnWsfPlEypRC5VWQuqHxM1y7JesS2IvtlOJK78cp7utyoWTZb2ZefNmEPqQk01OaH4mVdjcT6DVDqYNU4TUFX-FVnlJSVY0pHiNVoRQmtGKshP0LoR7QgjLKXuLTlhdVKzg1Qr9uRxn5yEosBFvzSCtDvjCym4EfCv9ADH9BjnAtABu4qwNBNw7j-MO8JWNXioYx3mUHp-PowsRvFH4i7Ha2AHfmAjY9Y_gNhl1P40FfA0K9jFptD_aa3qK3vRyDPD--K7R3eXFbfst237_etWebzNZlCRmfVqk667qOa-V7ouO0KJWJZeMd4SrhrGm0kpq6EjJKACnlS50I9MQQJcVW6PPB9393C25wWJ-FHtvJul_CyeN-HdizU4M7kHkhDUNSzGu0aejgne_ZghRTCYs50sLbg6CNozXjLOmTtDiAFXeheChf96TE7H0J1J_4qk_cewv0T6-9PhMeiosAcgB8Eh3s7cpsv9r_gX0Kq4M</recordid><startdate>20230727</startdate><enddate>20230727</enddate><creator>Huber, Max E.</creator><creator>Wurnig, Silas</creator><creator>Toy, Lara</creator><creator>Weiler, Corinna</creator><creator>Merten, Nicole</creator><creator>Kostenis, Evi</creator><creator>Hansen, Finn K.</creator><creator>Schiedel, Matthias</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8284-5514</orcidid><orcidid>https://orcid.org/0000-0001-6932-2217</orcidid><orcidid>https://orcid.org/0000-0001-7365-3617</orcidid><orcidid>https://orcid.org/0009-0009-6708-7415</orcidid><orcidid>https://orcid.org/0009-0006-7809-1426</orcidid><orcidid>https://orcid.org/0000-0002-8487-6805</orcidid><orcidid>https://orcid.org/0000-0003-3042-0463</orcidid><orcidid>https://orcid.org/0000-0001-9765-5975</orcidid></search><sort><creationdate>20230727</creationdate><title>Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2</title><author>Huber, Max E. ; Wurnig, Silas ; Toy, Lara ; Weiler, Corinna ; Merten, Nicole ; Kostenis, Evi ; Hansen, Finn K. ; Schiedel, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a450t-faced7b6f997cdf4b0247c59a39b09c83386dcadeb0532ee926d4d8ab09eed563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Allosteric Site</topic><topic>Ligands</topic><topic>Protein Binding</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Receptors, Interleukin-8B</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huber, Max E.</creatorcontrib><creatorcontrib>Wurnig, Silas</creatorcontrib><creatorcontrib>Toy, Lara</creatorcontrib><creatorcontrib>Weiler, Corinna</creatorcontrib><creatorcontrib>Merten, Nicole</creatorcontrib><creatorcontrib>Kostenis, Evi</creatorcontrib><creatorcontrib>Hansen, Finn K.</creatorcontrib><creatorcontrib>Schiedel, Matthias</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huber, Max E.</au><au>Wurnig, Silas</au><au>Toy, Lara</au><au>Weiler, Corinna</au><au>Merten, Nicole</au><au>Kostenis, Evi</au><au>Hansen, Finn K.</au><au>Schiedel, Matthias</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2023-07-27</date><risdate>2023</risdate><volume>66</volume><issue>14</issue><spage>9916</spage><epage>9933</epage><pages>9916-9933</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (1), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 (9a) as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner. Further, we show that 9a can be used as a tool to visualize intracellular target engagement for CXCR2 via fluorescence microscopy. Thus, our small-molecule-based fluorescent CXCR2 ligand 9a represents a promising tool for future studies of CXCR2 pharmacology.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>37463496</pmid><doi>10.1021/acs.jmedchem.3c00769</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-8284-5514</orcidid><orcidid>https://orcid.org/0000-0001-6932-2217</orcidid><orcidid>https://orcid.org/0000-0001-7365-3617</orcidid><orcidid>https://orcid.org/0009-0009-6708-7415</orcidid><orcidid>https://orcid.org/0009-0006-7809-1426</orcidid><orcidid>https://orcid.org/0000-0002-8487-6805</orcidid><orcidid>https://orcid.org/0000-0003-3042-0463</orcidid><orcidid>https://orcid.org/0000-0001-9765-5975</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2023-07, Vol.66 (14), p.9916-9933 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10388362 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Allosteric Site Ligands Protein Binding Receptors, G-Protein-Coupled - metabolism Receptors, Interleukin-8B |
| title | Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T19%3A38%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fluorescent%20Ligands%20Enable%20Target%20Engagement%20Studies%20for%20the%20Intracellular%20Allosteric%20Binding%20Site%20of%20the%20Chemokine%20Receptor%20CXCR2&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Huber,%20Max%20E.&rft.date=2023-07-27&rft.volume=66&rft.issue=14&rft.spage=9916&rft.epage=9933&rft.pages=9916-9933&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.3c00769&rft_dat=%3Cproquest_pubme%3E2839739387%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2839739387&rft_id=info:pmid/37463496&rfr_iscdi=true |