Synthesis and structure–activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors
Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2014-10, Vol.22 (19), p.5513-5529 |
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| creator | Nagao, Satoshi Yamane, Yoshinobu Funasaka, Setsuo Tanaka, Keigo Miyazaki, Kazuki Kotake, Yoshihiko Kamata, Jun-ichi Watanabe-Miyano, Saori Toyama, Osamu Ozawa, Yoichi Mizui, Yoshiharu Okamoto, Kiyoshi Ito, Daisuke |
| description | Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47nM, respectively), and in vivo. Additionally, 43a (12.5–100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight. |
| doi_str_mv | 10.1016/j.bmc.2014.07.020 |
| format | Article |
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HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47nM, respectively), and in vivo. 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All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-971269195563a6c5b687fd1cf91dc1e219476eff906547dec48bea8b253c6f6c3</citedby><cites>FETCH-LOGICAL-c423t-971269195563a6c5b687fd1cf91dc1e219476eff906547dec48bea8b253c6f6c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2014.07.020$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25139751$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nagao, Satoshi</creatorcontrib><creatorcontrib>Yamane, Yoshinobu</creatorcontrib><creatorcontrib>Funasaka, Setsuo</creatorcontrib><creatorcontrib>Tanaka, Keigo</creatorcontrib><creatorcontrib>Miyazaki, Kazuki</creatorcontrib><creatorcontrib>Kotake, Yoshihiko</creatorcontrib><creatorcontrib>Kamata, Jun-ichi</creatorcontrib><creatorcontrib>Watanabe-Miyano, Saori</creatorcontrib><creatorcontrib>Toyama, Osamu</creatorcontrib><creatorcontrib>Ozawa, Yoichi</creatorcontrib><creatorcontrib>Mizui, Yoshiharu</creatorcontrib><creatorcontrib>Okamoto, Kiyoshi</creatorcontrib><creatorcontrib>Ito, Daisuke</creatorcontrib><title>Synthesis and structure–activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47nM, respectively), and in vivo. Additionally, 43a (12.5–100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.</description><subject>Anilides - administration & dosage</subject><subject>Anilides - chemical synthesis</subject><subject>Anilides - chemistry</subject><subject>Anilides - pharmacology</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Dose-Response Relationship, Drug</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia-Inducible Factor 1 - antagonists & inhibitors</subject><subject>Hypoxia-inducible factor-1</subject><subject>Inhibitor</subject><subject>Molecular Structure</subject><subject>Small molecule</subject><subject>Small Molecule Libraries - administration & dosage</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Structure–activity relationships</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAQhi0EotvCA3BBPnJogiexnVicUAUFqRIH4Gw5zljrVdYOtrMiN96BN-RJSNnCkdOMNN__S_MR8gJYDQzk60M9HG3dMOA162rWsEdkB1zyqm0VPCY7pmRfsV7JC3KZ84Ex1nAFT8lFI6BVnYAdOX1eQ9lj9pmaMNJc0mLLkvDXj5_GFn_yZaUJJ1N8DHnv50yjoyGecLqmcywYyjWNyUzTSv_wSPfrHL97U_kwLtYPE1K3XWKqgPqw94Pf9vyMPHFmyvj8YV6Rr-_ffbn5UN19uv148_ausrxpS6U6aKQCJYRsjbRikH3nRrBOwWgBG1C8k-icYlLwbkTL-wFNPzSitdJJ216RV-feOcVvC-aijz5bnCYTMC5Zg5C8FQ2XYkPhjNoUc07o9Jz80aRVA9P3uvVBb7r1vW7NOr3p3jIvH-qX4Yjjv8Rfvxvw5gzg9uTJY9LZegwWR5_QFj1G_5_635z2k4I</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Nagao, Satoshi</creator><creator>Yamane, Yoshinobu</creator><creator>Funasaka, Setsuo</creator><creator>Tanaka, Keigo</creator><creator>Miyazaki, Kazuki</creator><creator>Kotake, Yoshihiko</creator><creator>Kamata, Jun-ichi</creator><creator>Watanabe-Miyano, Saori</creator><creator>Toyama, Osamu</creator><creator>Ozawa, Yoichi</creator><creator>Mizui, Yoshiharu</creator><creator>Okamoto, Kiyoshi</creator><creator>Ito, Daisuke</creator><general>Elsevier Ltd</general><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>20141001</creationdate><title>Synthesis and structure–activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors</title><author>Nagao, Satoshi ; 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| subjects | Anilides - administration & dosage Anilides - chemical synthesis Anilides - chemistry Anilides - pharmacology Cancer Cell Line, Tumor Dose-Response Relationship, Drug High-Throughput Screening Assays Humans Hypoxia Hypoxia-Inducible Factor 1 - antagonists & inhibitors Hypoxia-inducible factor-1 Inhibitor Molecular Structure Small molecule Small Molecule Libraries - administration & dosage Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship Structure–activity relationships |
| title | Synthesis and structure–activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors |
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