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New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development
Bromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the larg...
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| Published in: | Organic & biomolecular chemistry 2020-07, Vol.18 (27), p.5174-5182 |
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| container_end_page | 5182 |
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| container_title | Organic & biomolecular chemistry |
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| creator | Ycas, Peter D Zahid, Huda Chan, Alice Olson, Noelle M Johnson, Jorden A Talluri, Siva K Schonbrunn, Ernst Pomerantz, William C. K |
| description | Bromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the largest member of the nucleosome remodeling complex, NURF. Despite an emerging role for BPTF in regulating a diverse set of cancers, small molecule development for inhibiting the BPTF bromodomain has been lacking. Here we cross-validate three complementary biophysical assays to further the discovery of BPTF bromodomain inhibitors for chemical probe development: two direct binding assays (protein-observed
19
F (PrOF) NMR and surface plasmon resonance (SPR)) and a competitive inhibition assay (AlphaScreen). We first compare the assays using three small molecules and acetylated histone peptides with reported affinity for the BPTF bromodomain. Using SPR with both unlabeled and fluorinated BPTF, we further determine that there is a minimal effect of
19
F incorporation on ligand binding for future PrOF NMR experiments. To guide medicinal chemistry efforts towards chemical probe development, we subsequently evaluate two new BPTF inhibitor scaffolds with our suite of biophysical assays and rank-order compound affinities which could not otherwise be determined by PrOF NMR. Finally, we cocrystallize a subset of small molecule inhibitors and present the first published small molecule-protein structures with the BPTF bromodomain. We envision the biophysical assays described here and the structural insights from the crystallography will guide researchers towards developing selective and potent BPTF bromodomain inhibitors.
We report the first set of small molecule co-crystal structures with the bromodomain of BPTF and describe several new leads for chemical probe development. |
| doi_str_mv | 10.1039/d0ob00506a |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1039_D0OB00506A</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2423733716</sourcerecordid><originalsourceid>FETCH-LOGICAL-c524t-fc055a210b3100de6e8e20618b766312888a675ea4cb2366deab4b62728c24223</originalsourceid><addsrcrecordid>eNp9kctP3DAYxK2qqDwv3Fu56g1p4bOd2NlLJaDlISHgAGfLr-waJXGwE6r89xgWlvbSkz95fpoZaRDaJ3BIgM2PLAQNUAJXn9AWKYSYQcnmn9c3hU20ndIDAJkLXnxBm4yWVVVx2EKLa_cH-27ptR9CTLgOEQ9Lh09u786wjqENNrTKd9h1SjfOYj3hNMTRDGNUDdY-NGExYdXZl7tfTsmb_K9SUhO27sk1oW9dN-yijVo1ye29vTvo_uz33enF7Orm_PL0-GpmSloMs9pAWSpKQDMCYB13laPASaUF54zQ3FpxUTpVGE0Z59YpXWhOBa0MLShlO-jnyrcfdeusydG5p-yjb1WcZFBe_qt0fikX4UkKNme8gmzw480ghsfRpUE-hDF2ubPMAUwwJgjP1MGKMjGkFF29TiAgX0aRv-Dm5HWU4wx_-7vTGn1fIQNfV0BMZq1-rJr17__TZW9r9gy8HJ30</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2423733716</pqid></control><display><type>article</type><title>New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development</title><source>Royal Society of Chemistry:Jisc Collections:Royal Society of Chemistry Read and Publish 2022-2024 (reading list)</source><creator>Ycas, Peter D ; Zahid, Huda ; Chan, Alice ; Olson, Noelle M ; Johnson, Jorden A ; Talluri, Siva K ; Schonbrunn, Ernst ; Pomerantz, William C. K</creator><creatorcontrib>Ycas, Peter D ; Zahid, Huda ; Chan, Alice ; Olson, Noelle M ; Johnson, Jorden A ; Talluri, Siva K ; Schonbrunn, Ernst ; Pomerantz, William C. K</creatorcontrib><description>Bromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the largest member of the nucleosome remodeling complex, NURF. Despite an emerging role for BPTF in regulating a diverse set of cancers, small molecule development for inhibiting the BPTF bromodomain has been lacking. Here we cross-validate three complementary biophysical assays to further the discovery of BPTF bromodomain inhibitors for chemical probe development: two direct binding assays (protein-observed
19
F (PrOF) NMR and surface plasmon resonance (SPR)) and a competitive inhibition assay (AlphaScreen). We first compare the assays using three small molecules and acetylated histone peptides with reported affinity for the BPTF bromodomain. Using SPR with both unlabeled and fluorinated BPTF, we further determine that there is a minimal effect of
19
F incorporation on ligand binding for future PrOF NMR experiments. To guide medicinal chemistry efforts towards chemical probe development, we subsequently evaluate two new BPTF inhibitor scaffolds with our suite of biophysical assays and rank-order compound affinities which could not otherwise be determined by PrOF NMR. Finally, we cocrystallize a subset of small molecule inhibitors and present the first published small molecule-protein structures with the BPTF bromodomain. We envision the biophysical assays described here and the structural insights from the crystallography will guide researchers towards developing selective and potent BPTF bromodomain inhibitors.
We report the first set of small molecule co-crystal structures with the bromodomain of BPTF and describe several new leads for chemical probe development.</description><identifier>ISSN: 1477-0520</identifier><identifier>EISSN: 1477-0539</identifier><identifier>DOI: 10.1039/d0ob00506a</identifier><identifier>PMID: 32588860</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Affinity ; Antigens, Nuclear - chemistry ; Assaying ; Binding ; Biophysical Phenomena ; Chromatin ; Crystallography ; Inhibitors ; Magnetic Resonance Spectroscopy ; Nerve Tissue Proteins - antagonists & inhibitors ; Nerve Tissue Proteins - chemistry ; NMR ; Nuclear magnetic resonance ; Peptides ; Protein Domains ; Protein interaction ; Proteins ; Scaffolding ; Surface Plasmon Resonance ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - chemistry</subject><ispartof>Organic & biomolecular chemistry, 2020-07, Vol.18 (27), p.5174-5182</ispartof><rights>Copyright Royal Society of Chemistry 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-fc055a210b3100de6e8e20618b766312888a675ea4cb2366deab4b62728c24223</citedby><cites>FETCH-LOGICAL-c524t-fc055a210b3100de6e8e20618b766312888a675ea4cb2366deab4b62728c24223</cites><orcidid>0000-0002-0163-4078</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32588860$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ycas, Peter D</creatorcontrib><creatorcontrib>Zahid, Huda</creatorcontrib><creatorcontrib>Chan, Alice</creatorcontrib><creatorcontrib>Olson, Noelle M</creatorcontrib><creatorcontrib>Johnson, Jorden A</creatorcontrib><creatorcontrib>Talluri, Siva K</creatorcontrib><creatorcontrib>Schonbrunn, Ernst</creatorcontrib><creatorcontrib>Pomerantz, William C. K</creatorcontrib><title>New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development</title><title>Organic & biomolecular chemistry</title><addtitle>Org Biomol Chem</addtitle><description>Bromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the largest member of the nucleosome remodeling complex, NURF. Despite an emerging role for BPTF in regulating a diverse set of cancers, small molecule development for inhibiting the BPTF bromodomain has been lacking. Here we cross-validate three complementary biophysical assays to further the discovery of BPTF bromodomain inhibitors for chemical probe development: two direct binding assays (protein-observed
19
F (PrOF) NMR and surface plasmon resonance (SPR)) and a competitive inhibition assay (AlphaScreen). We first compare the assays using three small molecules and acetylated histone peptides with reported affinity for the BPTF bromodomain. Using SPR with both unlabeled and fluorinated BPTF, we further determine that there is a minimal effect of
19
F incorporation on ligand binding for future PrOF NMR experiments. To guide medicinal chemistry efforts towards chemical probe development, we subsequently evaluate two new BPTF inhibitor scaffolds with our suite of biophysical assays and rank-order compound affinities which could not otherwise be determined by PrOF NMR. Finally, we cocrystallize a subset of small molecule inhibitors and present the first published small molecule-protein structures with the BPTF bromodomain. We envision the biophysical assays described here and the structural insights from the crystallography will guide researchers towards developing selective and potent BPTF bromodomain inhibitors.
We report the first set of small molecule co-crystal structures with the bromodomain of BPTF and describe several new leads for chemical probe development.</description><subject>Affinity</subject><subject>Antigens, Nuclear - chemistry</subject><subject>Assaying</subject><subject>Binding</subject><subject>Biophysical Phenomena</subject><subject>Chromatin</subject><subject>Crystallography</subject><subject>Inhibitors</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Nerve Tissue Proteins - antagonists & inhibitors</subject><subject>Nerve Tissue Proteins - chemistry</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Peptides</subject><subject>Protein Domains</subject><subject>Protein interaction</subject><subject>Proteins</subject><subject>Scaffolding</subject><subject>Surface Plasmon Resonance</subject><subject>Transcription Factors - antagonists & inhibitors</subject><subject>Transcription Factors - chemistry</subject><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kctP3DAYxK2qqDwv3Fu56g1p4bOd2NlLJaDlISHgAGfLr-waJXGwE6r89xgWlvbSkz95fpoZaRDaJ3BIgM2PLAQNUAJXn9AWKYSYQcnmn9c3hU20ndIDAJkLXnxBm4yWVVVx2EKLa_cH-27ptR9CTLgOEQ9Lh09u786wjqENNrTKd9h1SjfOYj3hNMTRDGNUDdY-NGExYdXZl7tfTsmb_K9SUhO27sk1oW9dN-yijVo1ye29vTvo_uz33enF7Orm_PL0-GpmSloMs9pAWSpKQDMCYB13laPASaUF54zQ3FpxUTpVGE0Z59YpXWhOBa0MLShlO-jnyrcfdeusydG5p-yjb1WcZFBe_qt0fikX4UkKNme8gmzw480ghsfRpUE-hDF2ubPMAUwwJgjP1MGKMjGkFF29TiAgX0aRv-Dm5HWU4wx_-7vTGn1fIQNfV0BMZq1-rJr17__TZW9r9gy8HJ30</recordid><startdate>20200715</startdate><enddate>20200715</enddate><creator>Ycas, Peter D</creator><creator>Zahid, Huda</creator><creator>Chan, Alice</creator><creator>Olson, Noelle M</creator><creator>Johnson, Jorden A</creator><creator>Talluri, Siva K</creator><creator>Schonbrunn, Ernst</creator><creator>Pomerantz, William C. K</creator><general>Royal Society of Chemistry</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>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0163-4078</orcidid></search><sort><creationdate>20200715</creationdate><title>New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development</title><author>Ycas, Peter D ; Zahid, Huda ; Chan, Alice ; Olson, Noelle M ; Johnson, Jorden A ; Talluri, Siva K ; Schonbrunn, Ernst ; Pomerantz, William C. K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-fc055a210b3100de6e8e20618b766312888a675ea4cb2366deab4b62728c24223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Affinity</topic><topic>Antigens, Nuclear - chemistry</topic><topic>Assaying</topic><topic>Binding</topic><topic>Biophysical Phenomena</topic><topic>Chromatin</topic><topic>Crystallography</topic><topic>Inhibitors</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Nerve Tissue Proteins - antagonists & inhibitors</topic><topic>Nerve Tissue Proteins - chemistry</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Peptides</topic><topic>Protein Domains</topic><topic>Protein interaction</topic><topic>Proteins</topic><topic>Scaffolding</topic><topic>Surface Plasmon Resonance</topic><topic>Transcription Factors - antagonists & inhibitors</topic><topic>Transcription Factors - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ycas, Peter D</creatorcontrib><creatorcontrib>Zahid, Huda</creatorcontrib><creatorcontrib>Chan, Alice</creatorcontrib><creatorcontrib>Olson, Noelle M</creatorcontrib><creatorcontrib>Johnson, Jorden A</creatorcontrib><creatorcontrib>Talluri, Siva K</creatorcontrib><creatorcontrib>Schonbrunn, Ernst</creatorcontrib><creatorcontrib>Pomerantz, William C. K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ycas, Peter D</au><au>Zahid, Huda</au><au>Chan, Alice</au><au>Olson, Noelle M</au><au>Johnson, Jorden A</au><au>Talluri, Siva K</au><au>Schonbrunn, Ernst</au><au>Pomerantz, William C. K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development</atitle><jtitle>Organic & biomolecular chemistry</jtitle><addtitle>Org Biomol Chem</addtitle><date>2020-07-15</date><risdate>2020</risdate><volume>18</volume><issue>27</issue><spage>5174</spage><epage>5182</epage><pages>5174-5182</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><notes>10.1039/d0ob00506a</notes><notes>Electronic supplementary information (ESI) available. See DOI</notes><notes>These authors contributed equally to this manuscript.</notes><abstract>Bromodomain-containing proteins regulate transcription through protein-protein interactions with chromatin and serve as scaffolding proteins for recruiting essential members of the transcriptional machinery. One such protein is the bromodomain and PHD-containing transcription factor (BPTF), the largest member of the nucleosome remodeling complex, NURF. Despite an emerging role for BPTF in regulating a diverse set of cancers, small molecule development for inhibiting the BPTF bromodomain has been lacking. Here we cross-validate three complementary biophysical assays to further the discovery of BPTF bromodomain inhibitors for chemical probe development: two direct binding assays (protein-observed
19
F (PrOF) NMR and surface plasmon resonance (SPR)) and a competitive inhibition assay (AlphaScreen). We first compare the assays using three small molecules and acetylated histone peptides with reported affinity for the BPTF bromodomain. Using SPR with both unlabeled and fluorinated BPTF, we further determine that there is a minimal effect of
19
F incorporation on ligand binding for future PrOF NMR experiments. To guide medicinal chemistry efforts towards chemical probe development, we subsequently evaluate two new BPTF inhibitor scaffolds with our suite of biophysical assays and rank-order compound affinities which could not otherwise be determined by PrOF NMR. Finally, we cocrystallize a subset of small molecule inhibitors and present the first published small molecule-protein structures with the BPTF bromodomain. We envision the biophysical assays described here and the structural insights from the crystallography will guide researchers towards developing selective and potent BPTF bromodomain inhibitors.
We report the first set of small molecule co-crystal structures with the bromodomain of BPTF and describe several new leads for chemical probe development.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>32588860</pmid><doi>10.1039/d0ob00506a</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-0163-4078</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Royal Society of Chemistry:Jisc Collections:Royal Society of Chemistry Read and Publish 2022-2024 (reading list) |
| subjects | Affinity Antigens, Nuclear - chemistry Assaying Binding Biophysical Phenomena Chromatin Crystallography Inhibitors Magnetic Resonance Spectroscopy Nerve Tissue Proteins - antagonists & inhibitors Nerve Tissue Proteins - chemistry NMR Nuclear magnetic resonance Peptides Protein Domains Protein interaction Proteins Scaffolding Surface Plasmon Resonance Transcription Factors - antagonists & inhibitors Transcription Factors - chemistry |
| title | New inhibitors for the BPTF bromodomain enabled by structural biology and biophysical assay development |
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