Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors
Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitor...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (5), p.2015-2019 |
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| container_end_page | 2019 |
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| container_issue | 5 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 22 |
| creator | Cuny, Gregory D. Ulyanova, Natalia P. Patnaik, Debasis Liu, Ji-Feng Lin, Xiangjie Auerbach, Ken Ray, Soumya S. Xian, Jun Glicksman, Marcie A. Stein, Ross L. Higgins, Jonathan M.G. |
| description | Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure–activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented. |
| doi_str_mv | 10.1016/j.bmcl.2012.01.028 |
| format | Article |
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High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure–activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.01.028</identifier><identifier>PMID: 22335895</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Beta-carboline ; Biological and medical sciences ; Carbolines - chemistry ; Carbolines - metabolism ; Carbolines - pharmacology ; crystal structure ; Dyrk Kinases ; Haspin ; histones ; Humans ; Inhibitor ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinase ; liver ; Medical sciences ; Mice ; Microsomes, Liver - metabolism ; mitosis ; Models, Molecular ; Pharmacology. Drug treatments ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - metabolism ; protein-serine-threonine kinases ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - metabolism ; screening ; serine ; Structure-Activity Relationship ; structure-activity relationships ; threonine</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (5), p.2015-2019</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><rights>2012 Elsevier Ltd. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c606t-37ff0fbeb3e2f9b0974dce5f18784081bf70f4919235bb55dd02513f2b31fbef3</citedby><cites>FETCH-LOGICAL-c606t-37ff0fbeb3e2f9b0974dce5f18784081bf70f4919235bb55dd02513f2b31fbef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X12000522$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25627559$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22335895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cuny, Gregory D.</creatorcontrib><creatorcontrib>Ulyanova, Natalia P.</creatorcontrib><creatorcontrib>Patnaik, Debasis</creatorcontrib><creatorcontrib>Liu, Ji-Feng</creatorcontrib><creatorcontrib>Lin, Xiangjie</creatorcontrib><creatorcontrib>Auerbach, Ken</creatorcontrib><creatorcontrib>Ray, Soumya S.</creatorcontrib><creatorcontrib>Xian, Jun</creatorcontrib><creatorcontrib>Glicksman, Marcie A.</creatorcontrib><creatorcontrib>Stein, Ross L.</creatorcontrib><creatorcontrib>Higgins, Jonathan M.G.</creatorcontrib><title>Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure–activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.</description><subject>Animals</subject><subject>Beta-carboline</subject><subject>Biological and medical sciences</subject><subject>Carbolines - chemistry</subject><subject>Carbolines - metabolism</subject><subject>Carbolines - pharmacology</subject><subject>crystal structure</subject><subject>Dyrk Kinases</subject><subject>Haspin</subject><subject>histones</subject><subject>Humans</subject><subject>Inhibitor</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kinase</subject><subject>liver</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Microsomes, Liver - metabolism</subject><subject>mitosis</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>protein-serine-threonine kinases</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>screening</subject><subject>serine</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>threonine</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>eNqNksuKFDEUhgtRnHb0BVxobcRVtSfXqgIRZPAGAy7GAXchSZ1Mp62utEmqoXe-g2_ok5im21E34iqLfP-fc_hSVY8JLAkQ-WK9NBs7LikQugSyBNrdqRaES94wDuJutYBeQtP1_PNZ9SClNQDhwPn96oxSxkTXi0Wlr3KcbZ4j_vj2Xdvsdz7v64ijzj5MaeW3dcrzsK-Dqw1m3VgdTRj9hPWA0e8KtsNU61SvdNr6qf7iJ52w9tPKG59DTA-re06PCR-dzvPq-u2bTxfvm8uP7z5cvL5srASZG9Y6B86gYUhdb6Bv-WBRONK1HYeOGNeC4z3pKRPGCDEMQAVhjhpGSsyx8-rVsXc7mw2W7JSjHtU2-o2OexW0V3_fTH6lbsJOMdp1LWel4PmpIIavM6asNj5ZHEc9YZiT6qnsekLgf0jaSirlgaRH0saQUkR3Ow8BdZCo1uogUR0kKiCqSCyhJ39uchv5Za0Az06ATlaPLurJ-vSbE5K2QvSFe3rknA5K38TCXF-Vl0T5CUxCSwvx8khgMbPzGFWyHieLg49osxqC_9ekPwFj_8gr</recordid><startdate>20120301</startdate><enddate>20120301</enddate><creator>Cuny, Gregory D.</creator><creator>Ulyanova, Natalia P.</creator><creator>Patnaik, Debasis</creator><creator>Liu, Ji-Feng</creator><creator>Lin, Xiangjie</creator><creator>Auerbach, Ken</creator><creator>Ray, Soumya S.</creator><creator>Xian, Jun</creator><creator>Glicksman, Marcie A.</creator><creator>Stein, Ross L.</creator><creator>Higgins, Jonathan M.G.</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><scope>5PM</scope></search><sort><creationdate>20120301</creationdate><title>Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors</title><author>Cuny, Gregory D. ; Ulyanova, Natalia P. ; Patnaik, Debasis ; Liu, Ji-Feng ; Lin, Xiangjie ; Auerbach, Ken ; Ray, Soumya S. ; Xian, Jun ; Glicksman, Marcie A. ; Stein, Ross L. ; Higgins, Jonathan M.G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c606t-37ff0fbeb3e2f9b0974dce5f18784081bf70f4919235bb55dd02513f2b31fbef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Beta-carboline</topic><topic>Biological and medical sciences</topic><topic>Carbolines - chemistry</topic><topic>Carbolines - metabolism</topic><topic>Carbolines - pharmacology</topic><topic>crystal structure</topic><topic>Dyrk Kinases</topic><topic>Haspin</topic><topic>histones</topic><topic>Humans</topic><topic>Inhibitor</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kinase</topic><topic>liver</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>mitosis</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>protein-serine-threonine kinases</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>screening</topic><topic>serine</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>threonine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cuny, Gregory D.</creatorcontrib><creatorcontrib>Ulyanova, Natalia P.</creatorcontrib><creatorcontrib>Patnaik, Debasis</creatorcontrib><creatorcontrib>Liu, Ji-Feng</creatorcontrib><creatorcontrib>Lin, Xiangjie</creatorcontrib><creatorcontrib>Auerbach, Ken</creatorcontrib><creatorcontrib>Ray, Soumya S.</creatorcontrib><creatorcontrib>Xian, Jun</creatorcontrib><creatorcontrib>Glicksman, Marcie A.</creatorcontrib><creatorcontrib>Stein, Ross L.</creatorcontrib><creatorcontrib>Higgins, Jonathan M.G.</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cuny, Gregory D.</au><au>Ulyanova, Natalia P.</au><au>Patnaik, Debasis</au><au>Liu, Ji-Feng</au><au>Lin, Xiangjie</au><au>Auerbach, Ken</au><au>Ray, Soumya S.</au><au>Xian, Jun</au><au>Glicksman, Marcie A.</au><au>Stein, Ross L.</au><au>Higgins, Jonathan M.G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-03-01</date><risdate>2012</risdate><volume>22</volume><issue>5</issue><spage>2015</spage><epage>2019</epage><pages>2015-2019</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure–activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22335895</pmid><doi>10.1016/j.bmcl.2012.01.028</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (5), p.2015-2019 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Animals Beta-carboline Biological and medical sciences Carbolines - chemistry Carbolines - metabolism Carbolines - pharmacology crystal structure Dyrk Kinases Haspin histones Humans Inhibitor Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Kinase liver Medical sciences Mice Microsomes, Liver - metabolism mitosis Models, Molecular Pharmacology. Drug treatments Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism protein-serine-threonine kinases Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - metabolism screening serine Structure-Activity Relationship structure-activity relationships threonine |
| title | Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors |
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