An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase
Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators reliev...
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| Veröffentlicht in: | Chemistry & biology 2008-04, Vol.15 (4), p.322-331 |
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| creator | Deacon, Sean W. Beeser, Alexander Fukui, Jami A. Rennefahrt, Ulrike E.E. Myers, Cynthia Chernoff, Jonathan Peterson, Jeffrey R. |
| description | Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric
inhibitors targeting
Pak1
activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak. |
| doi_str_mv | 10.1016/j.chembiol.2008.03.005 |
| format | Article |
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inhibitors targeting
Pak1
activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.</description><identifier>ISSN: 1074-5521</identifier><identifier>EISSN: 1879-1301</identifier><identifier>DOI: 10.1016/j.chembiol.2008.03.005</identifier><identifier>PMID: 18420139</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Animals ; CHEMBIO ; Disulfides - chemistry ; Disulfides - metabolism ; Disulfides - pharmacology ; Drug Evaluation, Preclinical - methods ; Enzyme Activation - drug effects ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Homeostasis - drug effects ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - metabolism ; Mice ; Naphthols - chemistry ; Naphthols - metabolism ; Naphthols - pharmacology ; p21-Activated Kinases - antagonists & inhibitors ; p21-Activated Kinases - metabolism ; Platelet-Derived Growth Factor - metabolism ; Protein Conformation - drug effects ; Protein Kinase Inhibitors - metabolism ; Protein Kinase Inhibitors - pharmacology ; SIGNALING ; Small Molecule Libraries - metabolism ; Small Molecule Libraries - pharmacology ; Substrate Specificity</subject><ispartof>Chemistry & biology, 2008-04, Vol.15 (4), p.322-331</ispartof><rights>2008 Elsevier Ltd</rights><rights>2008 Elsevier Ltd. All rights reserved. 2008</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-b99707aaaa39a43ec6dbc3481850980c4ac40a967175979c0232106cfbb161c63</citedby><cites>FETCH-LOGICAL-c535t-b99707aaaa39a43ec6dbc3481850980c4ac40a967175979c0232106cfbb161c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.chembiol.2008.03.005$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18420139$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Deacon, Sean W.</creatorcontrib><creatorcontrib>Beeser, Alexander</creatorcontrib><creatorcontrib>Fukui, Jami A.</creatorcontrib><creatorcontrib>Rennefahrt, Ulrike E.E.</creatorcontrib><creatorcontrib>Myers, Cynthia</creatorcontrib><creatorcontrib>Chernoff, Jonathan</creatorcontrib><creatorcontrib>Peterson, Jeffrey R.</creatorcontrib><title>An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase</title><title>Chemistry & biology</title><addtitle>Chem Biol</addtitle><description>Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric
inhibitors targeting
Pak1
activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.</description><subject>Animals</subject><subject>CHEMBIO</subject><subject>Disulfides - chemistry</subject><subject>Disulfides - metabolism</subject><subject>Disulfides - pharmacology</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Enzyme Activation - drug effects</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Homeostasis - drug effects</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - metabolism</subject><subject>Mice</subject><subject>Naphthols - chemistry</subject><subject>Naphthols - metabolism</subject><subject>Naphthols - pharmacology</subject><subject>p21-Activated Kinases - antagonists & inhibitors</subject><subject>p21-Activated Kinases - metabolism</subject><subject>Platelet-Derived Growth Factor - metabolism</subject><subject>Protein Conformation - drug effects</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>SIGNALING</subject><subject>Small Molecule Libraries - metabolism</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Substrate Specificity</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhi0EomXhFSqfOJEwjmMnviBWFdAVrTi0nC3HmWy8JPFiJyv17fFqlwInLI3GGv_zjzUfIVcMcgZMvt_ltsexcX7IC4A6B54DiGfkktWVyhgH9jzdoSozIQp2QV7FuAMAViv5klywuiyAcXVJfqwnuom-82HM7nFAO7sDvqP3oxmG7M6nwjIg3Uy9a9zsA30wYYtzpHOPdL2kCm6XwaT8SO_Q9mZycaS-o_uCZeujmZmxpV_dZCK-Ji86M0R8c84r8v3zp4frm-z225fN9fo2s4KLOWuUqqAy6XBlSo5Wto3lZc1qAaoGWxpbglGyYpVQlbJQ8IKBtF3TMMms5Cvy4eS7X5oRW4vTHMyg98GNJjxqb5z-92Vyvd76gy654DLFirw9GwT_c8E469FFi8NgJvRL1FIxJkoBSShPQht8jAG7pyEM9JGT3unfnPSRkwauE6fUePX3F_-0ncEkwceTANOiDg6DjtbhZLF1IUHSrXf_m_ELkS2pBA</recordid><startdate>20080401</startdate><enddate>20080401</enddate><creator>Deacon, Sean W.</creator><creator>Beeser, Alexander</creator><creator>Fukui, Jami A.</creator><creator>Rennefahrt, Ulrike E.E.</creator><creator>Myers, Cynthia</creator><creator>Chernoff, Jonathan</creator><creator>Peterson, Jeffrey R.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><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></search><sort><creationdate>20080401</creationdate><title>An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase</title><author>Deacon, Sean W. ; Beeser, Alexander ; Fukui, Jami A. ; Rennefahrt, Ulrike E.E. ; Myers, Cynthia ; Chernoff, Jonathan ; Peterson, Jeffrey R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-b99707aaaa39a43ec6dbc3481850980c4ac40a967175979c0232106cfbb161c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>CHEMBIO</topic><topic>Disulfides - chemistry</topic><topic>Disulfides - metabolism</topic><topic>Disulfides - pharmacology</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Enzyme Activation - drug effects</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Homeostasis - drug effects</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - metabolism</topic><topic>Mice</topic><topic>Naphthols - chemistry</topic><topic>Naphthols - metabolism</topic><topic>Naphthols - pharmacology</topic><topic>p21-Activated Kinases - antagonists & inhibitors</topic><topic>p21-Activated Kinases - metabolism</topic><topic>Platelet-Derived Growth Factor - metabolism</topic><topic>Protein Conformation - drug effects</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>SIGNALING</topic><topic>Small Molecule Libraries - metabolism</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Substrate Specificity</topic><toplevel>online_resources</toplevel><creatorcontrib>Deacon, Sean W.</creatorcontrib><creatorcontrib>Beeser, Alexander</creatorcontrib><creatorcontrib>Fukui, Jami A.</creatorcontrib><creatorcontrib>Rennefahrt, Ulrike E.E.</creatorcontrib><creatorcontrib>Myers, Cynthia</creatorcontrib><creatorcontrib>Chernoff, Jonathan</creatorcontrib><creatorcontrib>Peterson, Jeffrey R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>Chemistry & biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Deacon, Sean W.</au><au>Beeser, Alexander</au><au>Fukui, Jami A.</au><au>Rennefahrt, Ulrike E.E.</au><au>Myers, Cynthia</au><au>Chernoff, Jonathan</au><au>Peterson, Jeffrey R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase</atitle><jtitle>Chemistry & biology</jtitle><addtitle>Chem Biol</addtitle><date>2008-04-01</date><risdate>2008</risdate><volume>15</volume><issue>4</issue><spage>322</spage><epage>331</epage><pages>322-331</pages><issn>1074-5521</issn><eissn>1879-1301</eissn><abstract>Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric
inhibitors targeting
Pak1
activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>18420139</pmid><doi>10.1016/j.chembiol.2008.03.005</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Animals CHEMBIO Disulfides - chemistry Disulfides - metabolism Disulfides - pharmacology Drug Evaluation, Preclinical - methods Enzyme Activation - drug effects Fibroblasts - drug effects Fibroblasts - metabolism Homeostasis - drug effects Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Mice Naphthols - chemistry Naphthols - metabolism Naphthols - pharmacology p21-Activated Kinases - antagonists & inhibitors p21-Activated Kinases - metabolism Platelet-Derived Growth Factor - metabolism Protein Conformation - drug effects Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology SIGNALING Small Molecule Libraries - metabolism Small Molecule Libraries - pharmacology Substrate Specificity |
| title | An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase |
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