Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2
5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure–activity relationships and a proposed ATP-competitive...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2010-01, Vol.18 (2), p.707-718 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Hilton, Stephen Naud, Sebastien Caldwell, John J. Boxall, Kathy Burns, Samantha Anderson, Victoria E. Antoni, Laurent Allen, Charlotte E. Pearl, Laurence H. Oliver, Antony W. Wynne Aherne, G. Garrett, Michelle D. Collins, Ian |
| description | 5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure–activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic ω-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2. |
| doi_str_mv | 10.1016/j.bmc.2009.11.058 |
| format | Article |
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Drug treatments ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2010-01, Vol.18 (2), p.707-718</ispartof><rights>2009 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2009 Elsevier Ltd. 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Rapid exploration of the hits through straightforward chemistry established structure–activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic ω-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.</description><subject>Aminopyridines - chemical synthesis</subject><subject>Aminopyridines - chemistry</subject><subject>Aminopyridines - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Checkpoint Kinase 2</subject><subject>CHK2</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>General aspects</subject><subject>High-throughput screening</subject><subject>Humans</subject><subject>Kinase inhibitor</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2LFDEQhoMo7rj6A7xIX8RTt_nqdBpPsvixsOBFwVtIqitMzU4nY9KzsP_eHmbUm6eCqud9KR7GXgveCS7M-10XZugk52MnRMd7-4RthDa6VWoUT9mGj8a23I7mir2odcc5l3oUz9nVGpGyF3zDft5OmBaKBH6hnBqfpga2vnhYsFA9L3NsZOtnSvnwWGiihA2lLQVacqmnK2wR7g-Z0tLcU_IVG_mSPYt-X_HVZV6zH58_fb_52t59-3J78_GuBWXl0moRdW90QKnkqEf0oPkQBqusDxJQSSFjr-Ukgh5CVGAhBjvBMFgjOIJR1-zdufdQ8q8j1sXNVAH3e58wH6sblNJ9L8y4kuJMQsm1FozuUGj25dEJ7k4-3c6tPt3JpxPCrT7XzJtL-zHMOP1N_BG4Am8vgK_g97H4BFT_cVKZQXK1ch_OHK4uHgiLq0CYACcqCIubMv3njd9JAZL1</recordid><startdate>20100115</startdate><enddate>20100115</enddate><creator>Hilton, Stephen</creator><creator>Naud, Sebastien</creator><creator>Caldwell, John J.</creator><creator>Boxall, Kathy</creator><creator>Burns, Samantha</creator><creator>Anderson, Victoria E.</creator><creator>Antoni, Laurent</creator><creator>Allen, Charlotte E.</creator><creator>Pearl, Laurence H.</creator><creator>Oliver, Antony W.</creator><creator>Wynne Aherne, G.</creator><creator>Garrett, Michelle D.</creator><creator>Collins, Ian</creator><general>Elsevier Ltd</general><general>Elsevier</general><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></search><sort><creationdate>20100115</creationdate><title>Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2</title><author>Hilton, Stephen ; Naud, Sebastien ; Caldwell, John J. ; Boxall, Kathy ; Burns, Samantha ; Anderson, Victoria E. ; Antoni, Laurent ; Allen, Charlotte E. ; Pearl, Laurence H. ; Oliver, Antony W. ; Wynne Aherne, G. ; Garrett, Michelle D. ; Collins, Ian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-41f4564be232949eac407b7838ab2ce3212f542d1b47bf3c8cfb8dc778610ec63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Aminopyridines - chemical synthesis</topic><topic>Aminopyridines - chemistry</topic><topic>Aminopyridines - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Checkpoint Kinase 2</topic><topic>CHK2</topic><topic>Crystallography</topic><topic>Crystallography, X-Ray</topic><topic>General aspects</topic><topic>High-throughput screening</topic><topic>Humans</topic><topic>Kinase inhibitor</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Pharmacology. 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| ispartof | Bioorganic & medicinal chemistry, 2010-01, Vol.18 (2), p.707-718 |
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| subjects | Aminopyridines - chemical synthesis Aminopyridines - chemistry Aminopyridines - pharmacology Antineoplastic agents Binding Sites Biological and medical sciences Cell Line Checkpoint Kinase 2 CHK2 Crystallography Crystallography, X-Ray General aspects High-throughput screening Humans Kinase inhibitor Medical sciences Models, Molecular Molecular Structure Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Stereoisomerism Structure-Activity Relationship |
| title | Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2 |
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