High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds
The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is imp...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2018-11, Vol.39 (11), p.1816-1822 |
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| container_title | Acta pharmacologica Sinica |
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| creator | Wang, Jia Gong, Grace Qun Zhou, Yan Lee, Woo-Jeong Buchanan, Christina Maree Denny, William Alexander Rewcastle, Gordon William Kendall, Jackie Diane Dickson, James Michael Jeremy Flanagan, Jack Urquhart Shepherd, Peter Robin Yang, De-Hua Wang, Ming-Wei |
| description | The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors. |
| doi_str_mv | 10.1038/s41401-018-0057-z |
| format | Article |
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Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-018-0057-z</identifier><identifier>PMID: 29991713</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; Amino acids ; Binding sites ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Drug discovery ; Enzyme inhibitors ; Enzymes ; Fluorescence ; Genetic transformation ; Glycerol ; High-throughput screening ; High-Throughput Screening Assays ; Humans ; Hydrogen Bonding ; Immunology ; Inhibitors ; Internal Medicine ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Kinases ; Libraries ; Lipid kinase ; Lipids ; Medical Microbiology ; Metabolism ; Molecular Docking Simulation ; Mutation ; Natural products ; Pharmacology/Toxicology ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Protein Binding ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - metabolism ; Proteins ; R&D ; Research & development ; Tumorigenesis ; Vaccine</subject><ispartof>Acta pharmacologica Sinica, 2018-11, Vol.39 (11), p.1816-1822</ispartof><rights>CPS and SIMM 2018</rights><rights>Copyright Nature Publishing Group Nov 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-796294b52cfbdbaac1a96aaa5a8bdfd81df8c6dabc56342705f571156a2ef6e73</citedby><cites>FETCH-LOGICAL-c470t-796294b52cfbdbaac1a96aaa5a8bdfd81df8c6dabc56342705f571156a2ef6e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289374/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289374/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29991713$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Jia</creatorcontrib><creatorcontrib>Gong, Grace Qun</creatorcontrib><creatorcontrib>Zhou, Yan</creatorcontrib><creatorcontrib>Lee, Woo-Jeong</creatorcontrib><creatorcontrib>Buchanan, Christina Maree</creatorcontrib><creatorcontrib>Denny, William Alexander</creatorcontrib><creatorcontrib>Rewcastle, Gordon William</creatorcontrib><creatorcontrib>Kendall, Jackie Diane</creatorcontrib><creatorcontrib>Dickson, James Michael Jeremy</creatorcontrib><creatorcontrib>Flanagan, Jack Urquhart</creatorcontrib><creatorcontrib>Shepherd, Peter Robin</creatorcontrib><creatorcontrib>Yang, De-Hua</creatorcontrib><creatorcontrib>Wang, Ming-Wei</creatorcontrib><title>High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Amino acids</subject><subject>Binding sites</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Drug discovery</subject><subject>Enzyme inhibitors</subject><subject>Enzymes</subject><subject>Fluorescence</subject><subject>Genetic transformation</subject><subject>Glycerol</subject><subject>High-throughput screening</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Immunology</subject><subject>Inhibitors</subject><subject>Internal Medicine</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Kinases</subject><subject>Libraries</subject><subject>Lipid kinase</subject><subject>Lipids</subject><subject>Medical Microbiology</subject><subject>Metabolism</subject><subject>Molecular Docking Simulation</subject><subject>Mutation</subject><subject>Natural products</subject><subject>Pharmacology/Toxicology</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Protein Binding</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Proteins</subject><subject>R&D</subject><subject>Research & development</subject><subject>Tumorigenesis</subject><subject>Vaccine</subject><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU1u1jAQhiNERUvhAGyQJTZsQm3HP8kGCVXAV1GpCMHamjh24iqxg-20onfgMFyEM5Hoa8uPxMoj-Zl3ZvQUxTOCXxFc1SeJEYZJiUldYsxlefOgOCKS8VJSzh6utZCkZLiuDovHKV1iXNGKNI-KQ9o0DZGkOiq-71w_lHmIYemHecko6WiMd75HGqYZXO8Tgh6cTxkB-nhWffj5A7kUbIgTag3EDc2DQTuCmfyEpiVDdsEj1xmfnXWmQ3PIWw0jcn5wrcshJnTt8oB8uDLjOhOsDWOXnhQHFsZknt6-x8WXd28_n-7K84v3Z6dvzkvNJM6lbARtWMuptm3XAmgCjQAADnXb2a4mna216KDVXFSMSswtl4RwAdRYYWR1XLze585LO5lOr9tFGNUc3QTxmwrg1N8_3g2qD1dK0LqpJFsDXt4GxPB1MSmrySVtxhG8CUtSFIu6YpLQDX3xD3oZlujX8xQllAtWE7ptRPaUjiGlaOz9MgSrTbbay1arbLXJVjdrz_M_r7jvuLO7AnQPpHnTZOLv0f9P_QVf5boO</recordid><startdate>20181101</startdate><enddate>20181101</enddate><creator>Wang, Jia</creator><creator>Gong, Grace Qun</creator><creator>Zhou, Yan</creator><creator>Lee, Woo-Jeong</creator><creator>Buchanan, Christina Maree</creator><creator>Denny, William Alexander</creator><creator>Rewcastle, Gordon William</creator><creator>Kendall, Jackie Diane</creator><creator>Dickson, James Michael Jeremy</creator><creator>Flanagan, Jack Urquhart</creator><creator>Shepherd, Peter Robin</creator><creator>Yang, De-Hua</creator><creator>Wang, Ming-Wei</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20181101</creationdate><title>High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds</title><author>Wang, Jia ; Gong, Grace Qun ; Zhou, Yan ; Lee, Woo-Jeong ; Buchanan, Christina Maree ; Denny, William Alexander ; Rewcastle, Gordon William ; Kendall, Jackie Diane ; Dickson, James Michael Jeremy ; Flanagan, Jack Urquhart ; Shepherd, Peter Robin ; Yang, De-Hua ; Wang, Ming-Wei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-796294b52cfbdbaac1a96aaa5a8bdfd81df8c6dabc56342705f571156a2ef6e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Amino acids</topic><topic>Binding sites</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Drug discovery</topic><topic>Enzyme inhibitors</topic><topic>Enzymes</topic><topic>Fluorescence</topic><topic>Genetic transformation</topic><topic>Glycerol</topic><topic>High-throughput screening</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Hydrogen Bonding</topic><topic>Immunology</topic><topic>Inhibitors</topic><topic>Internal Medicine</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Kinases</topic><topic>Libraries</topic><topic>Lipid kinase</topic><topic>Lipids</topic><topic>Medical Microbiology</topic><topic>Metabolism</topic><topic>Molecular Docking Simulation</topic><topic>Mutation</topic><topic>Natural products</topic><topic>Pharmacology/Toxicology</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Protein Binding</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Proteins</topic><topic>R&D</topic><topic>Research & development</topic><topic>Tumorigenesis</topic><topic>Vaccine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Jia</creatorcontrib><creatorcontrib>Gong, Grace Qun</creatorcontrib><creatorcontrib>Zhou, Yan</creatorcontrib><creatorcontrib>Lee, Woo-Jeong</creatorcontrib><creatorcontrib>Buchanan, Christina Maree</creatorcontrib><creatorcontrib>Denny, William Alexander</creatorcontrib><creatorcontrib>Rewcastle, Gordon William</creatorcontrib><creatorcontrib>Kendall, Jackie Diane</creatorcontrib><creatorcontrib>Dickson, James Michael Jeremy</creatorcontrib><creatorcontrib>Flanagan, Jack Urquhart</creatorcontrib><creatorcontrib>Shepherd, Peter Robin</creatorcontrib><creatorcontrib>Yang, De-Hua</creatorcontrib><creatorcontrib>Wang, Ming-Wei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Jia</au><au>Gong, Grace Qun</au><au>Zhou, Yan</au><au>Lee, Woo-Jeong</au><au>Buchanan, Christina Maree</au><au>Denny, William Alexander</au><au>Rewcastle, Gordon William</au><au>Kendall, Jackie Diane</au><au>Dickson, James Michael Jeremy</au><au>Flanagan, Jack Urquhart</au><au>Shepherd, Peter Robin</au><au>Yang, De-Hua</au><au>Wang, Ming-Wei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>39</volume><issue>11</issue><spage>1816</spage><epage>1822</epage><pages>1816-1822</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29991713</pmid><doi>10.1038/s41401-018-0057-z</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta pharmacologica Sinica, 2018-11, Vol.39 (11), p.1816-1822 |
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| subjects | 1-Phosphatidylinositol 3-kinase Amino acids Binding sites Biomedical and Life Sciences Biomedicine Cancer Drug discovery Enzyme inhibitors Enzymes Fluorescence Genetic transformation Glycerol High-throughput screening High-Throughput Screening Assays Humans Hydrogen Bonding Immunology Inhibitors Internal Medicine Isoenzymes - antagonists & inhibitors Isoenzymes - genetics Isoenzymes - metabolism Kinases Libraries Lipid kinase Lipids Medical Microbiology Metabolism Molecular Docking Simulation Mutation Natural products Pharmacology/Toxicology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Protein Binding Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Proteins R&D Research & development Tumorigenesis Vaccine |
| title | High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds |
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