Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors
Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against C...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (9), p.2590-2594 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Huang, Xiaohua Cheng, Cliff C. Fischmann, Thierry O. Duca, José S. Richards, Matthew Tadikonda, Praveen K. Reddy, Panduranga Adulla Zhao, Lianyun Arshad Siddiqui, M. Parry, David Davis, Nicole Seghezzi, Wolfgang Wiswell, Derek Shipps, Gerald W. |
| description | Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a ‘U-shaped’ topology and key interactions with the protein surface at the ATP site is also reported. |
| doi_str_mv | 10.1016/j.bmcl.2013.02.108 |
| format | Article |
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All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-564a01b9b9375da0b44a5a64a60331d6837f86c40aac5f3e972305106c0ea1ef3</citedby><cites>FETCH-LOGICAL-c380t-564a01b9b9375da0b44a5a64a60331d6837f86c40aac5f3e972305106c0ea1ef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X13002953$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23535330$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Xiaohua</creatorcontrib><creatorcontrib>Cheng, Cliff C.</creatorcontrib><creatorcontrib>Fischmann, Thierry O.</creatorcontrib><creatorcontrib>Duca, José S.</creatorcontrib><creatorcontrib>Richards, Matthew</creatorcontrib><creatorcontrib>Tadikonda, Praveen K.</creatorcontrib><creatorcontrib>Reddy, Panduranga Adulla</creatorcontrib><creatorcontrib>Zhao, Lianyun</creatorcontrib><creatorcontrib>Arshad Siddiqui, M.</creatorcontrib><creatorcontrib>Parry, David</creatorcontrib><creatorcontrib>Davis, Nicole</creatorcontrib><creatorcontrib>Seghezzi, Wolfgang</creatorcontrib><creatorcontrib>Wiswell, Derek</creatorcontrib><creatorcontrib>Shipps, Gerald W.</creatorcontrib><title>Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a ‘U-shaped’ topology and key interactions with the protein surface at the ATP site is also reported.</description><subject>2-Aminothiazole-4-carboxamide</subject><subject>adenosine triphosphate</subject><subject>Amides - chemical synthesis</subject><subject>Amides - chemistry</subject><subject>Amides - metabolism</subject><subject>Binding Sites</subject><subject>Checkpoint Kinase 1</subject><subject>chemistry</subject><subject>CHK1 protein kinase</subject><subject>Crystallography, X-Ray</subject><subject>cyclin-dependent kinase</subject><subject>Cyclin-Dependent Kinase 2 - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinase 2 - metabolism</subject><subject>Drug Design</subject><subject>drugs</subject><subject>Hybrid compounds</subject><subject>Molecular Docking Simulation</subject><subject>Protein Binding</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinases - chemistry</subject><subject>Protein Kinases - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Structure-based drug design</subject><subject>Thiazoles - chemistry</subject><subject>topology</subject><subject>X-ray diffraction</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1rFTEUhoMo9lr9Ay40SzdzPfmYL3Ajl9qKhS7agrtwJjnT5jIzuSYzfvTXN8OtLiWBwMtzXg5PGHsrYCtAVB_32260w1aCUFuQOWuesY3QlS6UhvI520BbQdG0-vsJe5XSHkBo0PolO5GqzEfBhu2v57jYeYlUdJjIcUfJ300cJ8fDYfajf8DZh4mHnssCRz-F-d7jQxio0IXF2IXfOXXEMXHkE_3idsCUVn538U1wP937zs8hptfsRY9DojdP7ym7_XJ2s7soLq_Ov-4-XxZWNTAXZaURRNd2rapLh9BpjSXmsAKlhKsaVfdNZTUg2rJX1NZSQSmgskAoqFen7MOx9xDDj4XSbEafLA0DThSWZISSdZ1vIzMqj6iNIaVIvTlEP2L8YwSY1bHZm9WxWR0bkDlr8tC7p_6lG8n9G_krNQPvj0CPweBd9MncXueGMn-AEq1eKz4dCcoefnqKJllPkyXnI9nZuOD_t8EjNB-V8Q</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Huang, Xiaohua</creator><creator>Cheng, Cliff C.</creator><creator>Fischmann, Thierry O.</creator><creator>Duca, José S.</creator><creator>Richards, Matthew</creator><creator>Tadikonda, Praveen K.</creator><creator>Reddy, Panduranga Adulla</creator><creator>Zhao, Lianyun</creator><creator>Arshad Siddiqui, M.</creator><creator>Parry, David</creator><creator>Davis, Nicole</creator><creator>Seghezzi, Wolfgang</creator><creator>Wiswell, Derek</creator><creator>Shipps, Gerald W.</creator><general>Elsevier Ltd</general><scope>FBQ</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>20130501</creationdate><title>Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors</title><author>Huang, Xiaohua ; Cheng, Cliff C. ; Fischmann, Thierry O. ; Duca, José S. ; Richards, Matthew ; Tadikonda, Praveen K. ; Reddy, Panduranga Adulla ; Zhao, Lianyun ; Arshad Siddiqui, M. ; Parry, David ; Davis, Nicole ; Seghezzi, Wolfgang ; Wiswell, Derek ; Shipps, Gerald W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-564a01b9b9375da0b44a5a64a60331d6837f86c40aac5f3e972305106c0ea1ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>2-Aminothiazole-4-carboxamide</topic><topic>adenosine triphosphate</topic><topic>Amides - chemical synthesis</topic><topic>Amides - chemistry</topic><topic>Amides - metabolism</topic><topic>Binding Sites</topic><topic>Checkpoint Kinase 1</topic><topic>chemistry</topic><topic>CHK1 protein kinase</topic><topic>Crystallography, X-Ray</topic><topic>cyclin-dependent kinase</topic><topic>Cyclin-Dependent Kinase 2 - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinase 2 - metabolism</topic><topic>Drug Design</topic><topic>drugs</topic><topic>Hybrid compounds</topic><topic>Molecular Docking Simulation</topic><topic>Protein Binding</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Protein Kinases - chemistry</topic><topic>Protein Kinases - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Structure-based drug design</topic><topic>Thiazoles - chemistry</topic><topic>topology</topic><topic>X-ray diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Xiaohua</creatorcontrib><creatorcontrib>Cheng, Cliff C.</creatorcontrib><creatorcontrib>Fischmann, Thierry O.</creatorcontrib><creatorcontrib>Duca, José S.</creatorcontrib><creatorcontrib>Richards, Matthew</creatorcontrib><creatorcontrib>Tadikonda, Praveen K.</creatorcontrib><creatorcontrib>Reddy, Panduranga Adulla</creatorcontrib><creatorcontrib>Zhao, Lianyun</creatorcontrib><creatorcontrib>Arshad Siddiqui, M.</creatorcontrib><creatorcontrib>Parry, David</creatorcontrib><creatorcontrib>Davis, Nicole</creatorcontrib><creatorcontrib>Seghezzi, Wolfgang</creatorcontrib><creatorcontrib>Wiswell, Derek</creatorcontrib><creatorcontrib>Shipps, Gerald W.</creatorcontrib><collection>AGRIS</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Xiaohua</au><au>Cheng, Cliff C.</au><au>Fischmann, Thierry O.</au><au>Duca, José S.</au><au>Richards, Matthew</au><au>Tadikonda, Praveen K.</au><au>Reddy, Panduranga Adulla</au><au>Zhao, Lianyun</au><au>Arshad Siddiqui, M.</au><au>Parry, David</au><au>Davis, Nicole</au><au>Seghezzi, Wolfgang</au><au>Wiswell, Derek</au><au>Shipps, Gerald W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>23</volume><issue>9</issue><spage>2590</spage><epage>2594</epage><pages>2590-2594</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a ‘U-shaped’ topology and key interactions with the protein surface at the ATP site is also reported.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23535330</pmid><doi>10.1016/j.bmcl.2013.02.108</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2590-2594 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 2-Aminothiazole-4-carboxamide adenosine triphosphate Amides - chemical synthesis Amides - chemistry Amides - metabolism Binding Sites Checkpoint Kinase 1 chemistry CHK1 protein kinase Crystallography, X-Ray cyclin-dependent kinase Cyclin-Dependent Kinase 2 - antagonists & inhibitors Cyclin-Dependent Kinase 2 - metabolism Drug Design drugs Hybrid compounds Molecular Docking Simulation Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinases - chemistry Protein Kinases - metabolism Structure-Activity Relationship Structure-based drug design Thiazoles - chemistry topology X-ray diffraction |
| title | Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors |
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