Orally Active Purine-Based Inhibitors of the Heat Shock Protein 90
Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-01, Vol.49 (2), p.817-828 |
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| container_title | Journal of medicinal chemistry |
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| creator | Biamonte, Marco A Shi, Jiandong Hong, Kevin Hurst, David C Zhang, Lin Fan, Junhua Busch, David J Karjian, Patricia L Maldonado, Angelica A Sensintaffar, John L Yang, Yong-Ching Kamal, Adeela Lough, Rachel E Lundgren, Karen Burrows, Francis J Timony, Gregg A Boehm, Marcus F Kasibhatla, Srinivas R |
| description | Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC50 = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H3PO4 salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage. |
| doi_str_mv | 10.1021/jm0503087 |
| format | Article |
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Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC50 = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H3PO4 salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0503087</identifier><identifier>PMID: 16420067</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Adenine - analogs & derivatives ; Adenine - chemical synthesis ; Adenine - chemistry ; Adenine - pharmacology ; Administration, Oral ; Animals ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Biological Availability ; Female ; General aspects ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; Medical sciences ; Mice ; Mice, Nude ; Pharmacology. Drug treatments ; Purines - chemical synthesis ; Purines - chemistry ; Purines - pharmacology ; Solubility ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2006-01, Vol.49 (2), p.817-828</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-bb4b48fdf02b040fdb2b45d3b21a14682dd79fa827045ee88a0802c64d0ac67f3</citedby><cites>FETCH-LOGICAL-a381t-bb4b48fdf02b040fdb2b45d3b21a14682dd79fa827045ee88a0802c64d0ac67f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm0503087$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0503087$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17433959$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16420067$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Biamonte, Marco A</creatorcontrib><creatorcontrib>Shi, Jiandong</creatorcontrib><creatorcontrib>Hong, Kevin</creatorcontrib><creatorcontrib>Hurst, David C</creatorcontrib><creatorcontrib>Zhang, Lin</creatorcontrib><creatorcontrib>Fan, Junhua</creatorcontrib><creatorcontrib>Busch, David J</creatorcontrib><creatorcontrib>Karjian, Patricia L</creatorcontrib><creatorcontrib>Maldonado, Angelica A</creatorcontrib><creatorcontrib>Sensintaffar, John L</creatorcontrib><creatorcontrib>Yang, Yong-Ching</creatorcontrib><creatorcontrib>Kamal, Adeela</creatorcontrib><creatorcontrib>Lough, Rachel E</creatorcontrib><creatorcontrib>Lundgren, Karen</creatorcontrib><creatorcontrib>Burrows, Francis J</creatorcontrib><creatorcontrib>Timony, Gregg A</creatorcontrib><creatorcontrib>Boehm, Marcus F</creatorcontrib><creatorcontrib>Kasibhatla, Srinivas R</creatorcontrib><title>Orally Active Purine-Based Inhibitors of the Heat Shock Protein 90</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC50 = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H3PO4 salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - chemical synthesis</subject><subject>Adenine - chemistry</subject><subject>Adenine - pharmacology</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Female</subject><subject>General aspects</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Pharmacology. Drug treatments</subject><subject>Purines - chemical synthesis</subject><subject>Purines - chemistry</subject><subject>Purines - pharmacology</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MtOwzAQBVALgaA8FvwA8gYkFoHxI7GzhIo3EhWFtWU7tuqSJmAnCP6eoFZ0w2oWc3Q1cxE6JHBGgJLz-QJyYCDFBhqRnELGJfBNNAKgNKMFZTtoN6U5ADBC2TbaIQWnAIUYocunqOv6G1_YLnw6POljaFx2qZOr8F0zCyZ0bUy49bibOXzrdIens9a-4UlsOxcaXMI-2vK6Tu5gNffQ6_XVy_g2e3y6uRtfPGaaSdJlxnDDpa88UAMcfGWo4XnFDCWa8ELSqhKl15IK4LlzUmqQQG3BK9C2EJ7toZNl7ntsP3qXOrUIybq61o1r-6TE8FDJiBjg6RLa2KYUnVfvMSx0_FYE1G9h6q-wwR6tQnuzcNVarhoawPEK6GR17aNubEhrJzhjZV4OLlu6kDr39bfX8U0NKSJXL5OpeoDrMUyfibpf52qb1LztYzN098-BPwNyiyI</recordid><startdate>20060126</startdate><enddate>20060126</enddate><creator>Biamonte, Marco A</creator><creator>Shi, Jiandong</creator><creator>Hong, Kevin</creator><creator>Hurst, David C</creator><creator>Zhang, Lin</creator><creator>Fan, Junhua</creator><creator>Busch, David J</creator><creator>Karjian, Patricia L</creator><creator>Maldonado, Angelica A</creator><creator>Sensintaffar, John L</creator><creator>Yang, Yong-Ching</creator><creator>Kamal, Adeela</creator><creator>Lough, Rachel E</creator><creator>Lundgren, Karen</creator><creator>Burrows, Francis J</creator><creator>Timony, Gregg A</creator><creator>Boehm, Marcus F</creator><creator>Kasibhatla, Srinivas R</creator><general>American Chemical Society</general><scope>BSCLL</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></search><sort><creationdate>20060126</creationdate><title>Orally Active Purine-Based Inhibitors of the Heat Shock Protein 90</title><author>Biamonte, Marco A ; Shi, Jiandong ; Hong, Kevin ; Hurst, David C ; Zhang, Lin ; Fan, Junhua ; Busch, David J ; Karjian, Patricia L ; Maldonado, Angelica A ; Sensintaffar, John L ; Yang, Yong-Ching ; Kamal, Adeela ; Lough, Rachel E ; Lundgren, Karen ; Burrows, Francis J ; Timony, Gregg A ; Boehm, Marcus F ; Kasibhatla, Srinivas R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-bb4b48fdf02b040fdb2b45d3b21a14682dd79fa827045ee88a0802c64d0ac67f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - chemical synthesis</topic><topic>Adenine - chemistry</topic><topic>Adenine - pharmacology</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Female</topic><topic>General aspects</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Pharmacology. Drug treatments</topic><topic>Purines - chemical synthesis</topic><topic>Purines - chemistry</topic><topic>Purines - pharmacology</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Biamonte, Marco A</creatorcontrib><creatorcontrib>Shi, Jiandong</creatorcontrib><creatorcontrib>Hong, Kevin</creatorcontrib><creatorcontrib>Hurst, David C</creatorcontrib><creatorcontrib>Zhang, Lin</creatorcontrib><creatorcontrib>Fan, Junhua</creatorcontrib><creatorcontrib>Busch, David J</creatorcontrib><creatorcontrib>Karjian, Patricia L</creatorcontrib><creatorcontrib>Maldonado, Angelica A</creatorcontrib><creatorcontrib>Sensintaffar, John L</creatorcontrib><creatorcontrib>Yang, Yong-Ching</creatorcontrib><creatorcontrib>Kamal, Adeela</creatorcontrib><creatorcontrib>Lough, Rachel E</creatorcontrib><creatorcontrib>Lundgren, Karen</creatorcontrib><creatorcontrib>Burrows, Francis J</creatorcontrib><creatorcontrib>Timony, Gregg A</creatorcontrib><creatorcontrib>Boehm, Marcus F</creatorcontrib><creatorcontrib>Kasibhatla, Srinivas R</creatorcontrib><collection>Istex</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Biamonte, Marco A</au><au>Shi, Jiandong</au><au>Hong, Kevin</au><au>Hurst, David C</au><au>Zhang, Lin</au><au>Fan, Junhua</au><au>Busch, David J</au><au>Karjian, Patricia L</au><au>Maldonado, Angelica A</au><au>Sensintaffar, John L</au><au>Yang, Yong-Ching</au><au>Kamal, Adeela</au><au>Lough, Rachel E</au><au>Lundgren, Karen</au><au>Burrows, Francis J</au><au>Timony, Gregg A</au><au>Boehm, Marcus F</au><au>Kasibhatla, Srinivas R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Orally Active Purine-Based Inhibitors of the Heat Shock Protein 90</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| ispartof | Journal of medicinal chemistry, 2006-01, Vol.49 (2), p.817-828 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Adenine - analogs & derivatives Adenine - chemical synthesis Adenine - chemistry Adenine - pharmacology Administration, Oral Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Biological Availability Female General aspects HSP90 Heat-Shock Proteins - antagonists & inhibitors Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Purines - chemical synthesis Purines - chemistry Purines - pharmacology Solubility Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Orally Active Purine-Based Inhibitors of the Heat Shock Protein 90 |
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