A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation
We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide...
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| Veröffentlicht in: | Nature chemical biology 2012-04, Vol.8 (6), p.576 |
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| creator | Bergamini, Giovanna Bell, Kathryn Shimamura, Satoko Werner, Thilo Cansfield, Andrew Müller, Katrin Perrin, Jessica Rau, Christina Ellard, Katie Hopf, Carsten Doce, Carola Leggate, Daniel Mangano, Raffaella Mathieson, Toby O'Mahony, Alison Plavec, Ivan Rharbaoui, Faiza Reinhard, Friedrich Savitski, Mikhail M Ramsden, Nigel Hirsch, Emilio Drewes, Gerard Rausch, Oliver Bantscheff, Marcus Neubauer, Gitte |
| description | We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases. |
| doi_str_mv | 10.1038/nchembio.957 |
| format | Article |
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Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.</description><identifier>EISSN: 1552-4469</identifier><identifier>DOI: 10.1038/nchembio.957</identifier><identifier>PMID: 22544264</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ; Arthritis, Experimental - drug therapy ; Arthritis, Experimental - immunology ; Arthritis, Experimental - pathology ; Binding, Competitive ; Cell Differentiation - drug effects ; Cell Line ; Cell Movement - drug effects ; Class Ib Phosphatidylinositol 3-Kinase - antagonists & inhibitors ; Drug Discovery ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Humans ; Interleukin-17 - immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Molecular Structure ; Rats ; Rats, Wistar ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacokinetics ; Small Molecule Libraries - pharmacology ; Small Molecule Libraries - therapeutic use ; Structure-Activity Relationship ; T-Lymphocytes, Helper-Inducer - cytology ; T-Lymphocytes, Helper-Inducer - drug effects ; T-Lymphocytes, Helper-Inducer - enzymology ; T-Lymphocytes, Helper-Inducer - immunology</subject><ispartof>Nature chemical biology, 2012-04, Vol.8 (6), p.576</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22544264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bergamini, Giovanna</creatorcontrib><creatorcontrib>Bell, Kathryn</creatorcontrib><creatorcontrib>Shimamura, Satoko</creatorcontrib><creatorcontrib>Werner, Thilo</creatorcontrib><creatorcontrib>Cansfield, Andrew</creatorcontrib><creatorcontrib>Müller, Katrin</creatorcontrib><creatorcontrib>Perrin, Jessica</creatorcontrib><creatorcontrib>Rau, Christina</creatorcontrib><creatorcontrib>Ellard, Katie</creatorcontrib><creatorcontrib>Hopf, Carsten</creatorcontrib><creatorcontrib>Doce, Carola</creatorcontrib><creatorcontrib>Leggate, Daniel</creatorcontrib><creatorcontrib>Mangano, Raffaella</creatorcontrib><creatorcontrib>Mathieson, Toby</creatorcontrib><creatorcontrib>O'Mahony, Alison</creatorcontrib><creatorcontrib>Plavec, Ivan</creatorcontrib><creatorcontrib>Rharbaoui, Faiza</creatorcontrib><creatorcontrib>Reinhard, Friedrich</creatorcontrib><creatorcontrib>Savitski, Mikhail M</creatorcontrib><creatorcontrib>Ramsden, Nigel</creatorcontrib><creatorcontrib>Hirsch, Emilio</creatorcontrib><creatorcontrib>Drewes, Gerard</creatorcontrib><creatorcontrib>Rausch, Oliver</creatorcontrib><creatorcontrib>Bantscheff, Marcus</creatorcontrib><creatorcontrib>Neubauer, Gitte</creatorcontrib><title>A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation</title><title>Nature chemical biology</title><addtitle>Nat Chem Biol</addtitle><description>We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. 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| fulltext | fulltext |
| identifier | EISSN: 1552-4469 |
| ispartof | Nature chemical biology, 2012-04, Vol.8 (6), p.576 |
| issn | 1552-4469 |
| language | eng |
| recordid | cdi_pubmed_primary_22544264 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Arthritis, Experimental - drug therapy Arthritis, Experimental - immunology Arthritis, Experimental - pathology Binding, Competitive Cell Differentiation - drug effects Cell Line Cell Movement - drug effects Class Ib Phosphatidylinositol 3-Kinase - antagonists & inhibitors Drug Discovery Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Humans Interleukin-17 - immunology Male Mice Mice, Inbred C57BL Mice, Inbred DBA Molecular Structure Rats Rats, Wistar Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacokinetics Small Molecule Libraries - pharmacology Small Molecule Libraries - therapeutic use Structure-Activity Relationship T-Lymphocytes, Helper-Inducer - cytology T-Lymphocytes, Helper-Inducer - drug effects T-Lymphocytes, Helper-Inducer - enzymology T-Lymphocytes, Helper-Inducer - immunology |
| title | A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation |
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