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Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors
[Display omitted] Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound...
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| Published in: | Bioorganic & medicinal chemistry letters 2017-03, Vol.27 (5), p.1311-1315 |
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c337t-2d05b17373b337459cbf592bed283971323936d1f4cddd7b7560b58cdc44be363 |
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| cites | cdi_FETCH-LOGICAL-c337t-2d05b17373b337459cbf592bed283971323936d1f4cddd7b7560b58cdc44be363 |
| container_end_page | 1315 |
| container_issue | 5 |
| container_start_page | 1311 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 27 |
| creator | Kiryanov, Andre Natala, Srinivasa Jones, Benjamin McBride, Christopher Feher, Victoria Lam, Betty Liu, Yan Honda, Kouhei Uchiyama, Noriko Kawamoto, Tomohiro Hikichi, Yuichi Zhang, Lilly Hosfield, David Skene, Robert Zou, Hua Stafford, Jeffrey Cao, Xiaodong Ichikawa, Takashi |
| description | [Display omitted]
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model. |
| doi_str_mv | 10.1016/j.bmcl.2016.10.009 |
| format | article |
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Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.10.009</identifier><identifier>PMID: 28169164</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antitumor activity ; Cell Cycle Proteins - antagonists & inhibitors ; Drug Design ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Female ; Heterografts ; HT29 Cells ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Mice ; Molecular Structure ; Multidrug resistance ; PLK1 inhibitor ; Polo-Like Kinase 1 ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Proto-Oncogene Proteins - antagonists & inhibitors ; Pteridines - chemical synthesis ; Pteridines - chemistry ; Pteridines - pharmacology ; Structure-Activity Relationship ; Structure-based drug design</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-03, Vol.27 (5), p.1311-1315</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c337t-2d05b17373b337459cbf592bed283971323936d1f4cddd7b7560b58cdc44be363</citedby><cites>FETCH-LOGICAL-c337t-2d05b17373b337459cbf592bed283971323936d1f4cddd7b7560b58cdc44be363</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28169164$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kiryanov, Andre</creatorcontrib><creatorcontrib>Natala, Srinivasa</creatorcontrib><creatorcontrib>Jones, Benjamin</creatorcontrib><creatorcontrib>McBride, Christopher</creatorcontrib><creatorcontrib>Feher, Victoria</creatorcontrib><creatorcontrib>Lam, Betty</creatorcontrib><creatorcontrib>Liu, Yan</creatorcontrib><creatorcontrib>Honda, Kouhei</creatorcontrib><creatorcontrib>Uchiyama, Noriko</creatorcontrib><creatorcontrib>Kawamoto, Tomohiro</creatorcontrib><creatorcontrib>Hikichi, Yuichi</creatorcontrib><creatorcontrib>Zhang, Lilly</creatorcontrib><creatorcontrib>Hosfield, David</creatorcontrib><creatorcontrib>Skene, Robert</creatorcontrib><creatorcontrib>Zou, Hua</creatorcontrib><creatorcontrib>Stafford, Jeffrey</creatorcontrib><creatorcontrib>Cao, Xiaodong</creatorcontrib><creatorcontrib>Ichikawa, Takashi</creatorcontrib><title>Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. 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Natala, Srinivasa ; Jones, Benjamin ; McBride, Christopher ; Feher, Victoria ; Lam, Betty ; Liu, Yan ; Honda, Kouhei ; Uchiyama, Noriko ; Kawamoto, Tomohiro ; Hikichi, Yuichi ; Zhang, Lilly ; Hosfield, David ; Skene, Robert ; Zou, Hua ; Stafford, Jeffrey ; Cao, Xiaodong ; Ichikawa, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c337t-2d05b17373b337459cbf592bed283971323936d1f4cddd7b7560b58cdc44be363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antitumor activity</topic><topic>Cell Cycle Proteins - antagonists & inhibitors</topic><topic>Drug Design</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Heterografts</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Multidrug resistance</topic><topic>PLK1 inhibitor</topic><topic>Polo-Like Kinase 1</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Pteridines - chemical synthesis</topic><topic>Pteridines - chemistry</topic><topic>Pteridines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Structure-based drug design</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kiryanov, Andre</creatorcontrib><creatorcontrib>Natala, Srinivasa</creatorcontrib><creatorcontrib>Jones, Benjamin</creatorcontrib><creatorcontrib>McBride, Christopher</creatorcontrib><creatorcontrib>Feher, Victoria</creatorcontrib><creatorcontrib>Lam, Betty</creatorcontrib><creatorcontrib>Liu, Yan</creatorcontrib><creatorcontrib>Honda, Kouhei</creatorcontrib><creatorcontrib>Uchiyama, Noriko</creatorcontrib><creatorcontrib>Kawamoto, Tomohiro</creatorcontrib><creatorcontrib>Hikichi, Yuichi</creatorcontrib><creatorcontrib>Zhang, Lilly</creatorcontrib><creatorcontrib>Hosfield, David</creatorcontrib><creatorcontrib>Skene, Robert</creatorcontrib><creatorcontrib>Zou, Hua</creatorcontrib><creatorcontrib>Stafford, Jeffrey</creatorcontrib><creatorcontrib>Cao, Xiaodong</creatorcontrib><creatorcontrib>Ichikawa, Takashi</creatorcontrib><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>Kiryanov, Andre</au><au>Natala, Srinivasa</au><au>Jones, Benjamin</au><au>McBride, Christopher</au><au>Feher, Victoria</au><au>Lam, Betty</au><au>Liu, Yan</au><au>Honda, Kouhei</au><au>Uchiyama, Noriko</au><au>Kawamoto, Tomohiro</au><au>Hikichi, Yuichi</au><au>Zhang, Lilly</au><au>Hosfield, David</au><au>Skene, Robert</au><au>Zou, Hua</au><au>Stafford, Jeffrey</au><au>Cao, Xiaodong</au><au>Ichikawa, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-03-01</date><risdate>2017</risdate><volume>27</volume><issue>5</issue><spage>1311</spage><epage>1315</epage><pages>1311-1315</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28169164</pmid><doi>10.1016/j.bmcl.2016.10.009</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2017-03, Vol.27 (5), p.1311-1315 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | ScienceDirect Freedom Collection |
| subjects | Animals Antitumor activity Cell Cycle Proteins - antagonists & inhibitors Drug Design Enzyme Activation - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Female Heterografts HT29 Cells Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Mice Molecular Structure Multidrug resistance PLK1 inhibitor Polo-Like Kinase 1 Protein Serine-Threonine Kinases - antagonists & inhibitors Proto-Oncogene Proteins - antagonists & inhibitors Pteridines - chemical synthesis Pteridines - chemistry Pteridines - pharmacology Structure-Activity Relationship Structure-based drug design |
| title | Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors |
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