Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series
Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.613-618 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Oubrie, Arthur Kaptein, Allard de Zwart, Edwin Hoogenboom, Niels Goorden, Rianne van de Kar, Bas van Hoek, Maaike de Kimpe, Vera van der Heijden, Ruud Borsboom, Judith Kazemier, Bert de Roos, Jeroen Scheffers, Michiel Lommerse, Jos Schultz-Fademrecht, Carsten Barf, Tjeerd |
| description | Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series. |
| doi_str_mv | 10.1016/j.bmcl.2011.10.071 |
| format | Article |
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Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.10.071</identifier><identifier>PMID: 22119462</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>adenosine triphosphate ; Anti-TNFα ; Benzamides - pharmacology ; Biological and medical sciences ; Chemistry, Pharmaceutical - methods ; Computer Simulation ; Crystallography, X-Ray - methods ; Cytokines - metabolism ; Drug Design ; HSP27 ; HSP27 Heat-Shock Proteins - metabolism ; Humans ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - pharmacology ; MAPKAPK2 ; Medical sciences ; MK2 ; Models, Chemical ; Pharmacology. Drug treatments ; Phosphorylation ; Piperidones - pharmacology ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - pharmacology ; Pyrroles - chemistry ; Rheumatoid arthritis ; tumor necrosis factor-alpha ; Tumor Necrosis Factor-alpha - metabolism ; X-ray diffraction</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-01, Vol.22 (1), p.613-618</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-8f2ab011a680bd2cafe72daeeef9ec2b0f2c0ecaa8d823c7f3f5e5e5e00357873</citedby><cites>FETCH-LOGICAL-c441t-8f2ab011a680bd2cafe72daeeef9ec2b0f2c0ecaa8d823c7f3f5e5e5e00357873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11014697$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25413382$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22119462$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oubrie, Arthur</creatorcontrib><creatorcontrib>Kaptein, Allard</creatorcontrib><creatorcontrib>de Zwart, Edwin</creatorcontrib><creatorcontrib>Hoogenboom, Niels</creatorcontrib><creatorcontrib>Goorden, Rianne</creatorcontrib><creatorcontrib>van de Kar, Bas</creatorcontrib><creatorcontrib>van Hoek, Maaike</creatorcontrib><creatorcontrib>de Kimpe, Vera</creatorcontrib><creatorcontrib>van der Heijden, Ruud</creatorcontrib><creatorcontrib>Borsboom, Judith</creatorcontrib><creatorcontrib>Kazemier, Bert</creatorcontrib><creatorcontrib>de Roos, Jeroen</creatorcontrib><creatorcontrib>Scheffers, Michiel</creatorcontrib><creatorcontrib>Lommerse, Jos</creatorcontrib><creatorcontrib>Schultz-Fademrecht, Carsten</creatorcontrib><creatorcontrib>Barf, Tjeerd</creatorcontrib><title>Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.</description><subject>adenosine triphosphate</subject><subject>Anti-TNFα</subject><subject>Benzamides - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray - methods</subject><subject>Cytokines - metabolism</subject><subject>Drug Design</subject><subject>HSP27</subject><subject>HSP27 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - pharmacology</subject><subject>MAPKAPK2</subject><subject>Medical sciences</subject><subject>MK2</subject><subject>Models, Chemical</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Piperidones - pharmacology</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - pharmacology</subject><subject>Pyrroles - chemistry</subject><subject>Rheumatoid arthritis</subject><subject>tumor necrosis factor-alpha</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>X-ray diffraction</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi0EokvhD3AAXxCnLGPHcRKJS1XxJcqHRCtxsxxn3HiVxIvtLOq_x9EucEPIB1ujZ8bvvC8hTxlsGTD5arftJjNuOTCWC1uo2T2yYUKKohRQ3ScbaCUUTSu-n5FHMe4AmAAhHpIzzhlrheQbsvvsDzjSi-uv1Phpj8kld0D66SOnbh5c55IPkf50aaB7n3BOtHPeDDg5o0eq554aHMei0xF7qk1udumOpiH45XbwS8pPpBGDw_iYPLB6jPjkdJ-Tm7dvri_fF1df3n24vLgqjBAsFY3lussradlA13OjLda814hoWzS8A8sNoNG66RtemtqWtsL1AJRV3dTlOXl5nLsP_seCManJxVWlntEvUbWsASl5Jf-DLEsma1lmkh9JE3yMAa3aBzfpcKcYqDUMtVNrGGoNY63lMHLTs9P4pZuw_9Py2_0MvDgBOmY7bdCzcfEvV4ksoFm550fOaq_0bcjMzbf8U5UTzTvDqu_1kcBs7MFhUNE4nA32LqBJqvfuX0p_AZw9srE</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Oubrie, Arthur</creator><creator>Kaptein, Allard</creator><creator>de Zwart, Edwin</creator><creator>Hoogenboom, Niels</creator><creator>Goorden, Rianne</creator><creator>van de Kar, Bas</creator><creator>van Hoek, Maaike</creator><creator>de Kimpe, Vera</creator><creator>van der Heijden, Ruud</creator><creator>Borsboom, Judith</creator><creator>Kazemier, Bert</creator><creator>de Roos, Jeroen</creator><creator>Scheffers, Michiel</creator><creator>Lommerse, Jos</creator><creator>Schultz-Fademrecht, Carsten</creator><creator>Barf, Tjeerd</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120101</creationdate><title>Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series</title><author>Oubrie, Arthur ; Kaptein, Allard ; de Zwart, Edwin ; Hoogenboom, Niels ; Goorden, Rianne ; van de Kar, Bas ; van Hoek, Maaike ; de Kimpe, Vera ; van der Heijden, Ruud ; Borsboom, Judith ; Kazemier, Bert ; de Roos, Jeroen ; Scheffers, Michiel ; Lommerse, Jos ; Schultz-Fademrecht, Carsten ; Barf, Tjeerd</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-8f2ab011a680bd2cafe72daeeef9ec2b0f2c0ecaa8d823c7f3f5e5e5e00357873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>adenosine triphosphate</topic><topic>Anti-TNFα</topic><topic>Benzamides - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Computer Simulation</topic><topic>Crystallography, X-Ray - methods</topic><topic>Cytokines - metabolism</topic><topic>Drug Design</topic><topic>HSP27</topic><topic>HSP27 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - pharmacology</topic><topic>MAPKAPK2</topic><topic>Medical sciences</topic><topic>MK2</topic><topic>Models, Chemical</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphorylation</topic><topic>Piperidones - pharmacology</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - pharmacology</topic><topic>Pyrroles - chemistry</topic><topic>Rheumatoid arthritis</topic><topic>tumor necrosis factor-alpha</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>X-ray diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oubrie, Arthur</creatorcontrib><creatorcontrib>Kaptein, Allard</creatorcontrib><creatorcontrib>de Zwart, Edwin</creatorcontrib><creatorcontrib>Hoogenboom, Niels</creatorcontrib><creatorcontrib>Goorden, Rianne</creatorcontrib><creatorcontrib>van de Kar, Bas</creatorcontrib><creatorcontrib>van Hoek, Maaike</creatorcontrib><creatorcontrib>de Kimpe, Vera</creatorcontrib><creatorcontrib>van der Heijden, Ruud</creatorcontrib><creatorcontrib>Borsboom, Judith</creatorcontrib><creatorcontrib>Kazemier, Bert</creatorcontrib><creatorcontrib>de Roos, Jeroen</creatorcontrib><creatorcontrib>Scheffers, Michiel</creatorcontrib><creatorcontrib>Lommerse, Jos</creatorcontrib><creatorcontrib>Schultz-Fademrecht, Carsten</creatorcontrib><creatorcontrib>Barf, Tjeerd</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oubrie, Arthur</au><au>Kaptein, Allard</au><au>de Zwart, Edwin</au><au>Hoogenboom, Niels</au><au>Goorden, Rianne</au><au>van de Kar, Bas</au><au>van Hoek, Maaike</au><au>de Kimpe, Vera</au><au>van der Heijden, Ruud</au><au>Borsboom, Judith</au><au>Kazemier, Bert</au><au>de Roos, Jeroen</au><au>Scheffers, Michiel</au><au>Lommerse, Jos</au><au>Schultz-Fademrecht, Carsten</au><au>Barf, Tjeerd</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>22</volume><issue>1</issue><spage>613</spage><epage>618</epage><pages>613-618</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22119462</pmid><doi>10.1016/j.bmcl.2011.10.071</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-01, Vol.22 (1), p.613-618 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_918066256 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | adenosine triphosphate Anti-TNFα Benzamides - pharmacology Biological and medical sciences Chemistry, Pharmaceutical - methods Computer Simulation Crystallography, X-Ray - methods Cytokines - metabolism Drug Design HSP27 HSP27 Heat-Shock Proteins - metabolism Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - pharmacology MAPKAPK2 Medical sciences MK2 Models, Chemical Pharmacology. Drug treatments Phosphorylation Piperidones - pharmacology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - pharmacology Pyrroles - chemistry Rheumatoid arthritis tumor necrosis factor-alpha Tumor Necrosis Factor-alpha - metabolism X-ray diffraction |
| title | Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series |
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