A novel p21 attenuator which is structurally related to sorafenib
p21 is a member of the cyclin kinase inhibitor family of proteins and plays pivotal roles in cellular proliferation as well as in the regulation of apoptosis, and thus has diverse functions in diseases as varied as cancer and atherosclerosis. In light of its pleiotropic effects and potential clinica...
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| Veröffentlicht in: | Cancer biology & therapy 2013-03, Vol.14 (3), p.278-285 |
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| container_title | Cancer biology & therapy |
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| creator | Wettersten, Hiromi I. Hee Hwang, Sung Li, Cuiwen Shiu, Eunice Y. Wecksler, Aaron T. Hammock, Bruce D. Weiss, Robert H. |
| description | p21 is a member of the cyclin kinase inhibitor family of proteins and plays pivotal roles in cellular proliferation as well as in the regulation of apoptosis, and thus has diverse functions in diseases as varied as cancer and atherosclerosis. In light of its pleiotropic effects and potential clinical relevance, new methods of attenuation of p21 protein levels by selective inhibitors are therefore powerful tools to probe malignant, infectious and other diseases. Here we introduce a novel p21 attenuator, UC2288, which possesses consistent and relatively selective activity for p21. UC2288 was synthesized based on the chemical model of sorafenib, a multikinase inhibitor that also attenuates p21, but unlike sorafenib, UC2288 did not inhibit Raf kinases or alter p-ERK protein levels. UC2288 decreased p21 mRNA expression independently of p53, and attenuated p21 protein levels with minimal effect on p21 protein stability. In addition, UC2288 inhibits cell growth in the kidney cancer cell lines (GI
50
= approximately 10 µM) as well as multiple other cancer cell lines. Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic. |
| doi_str_mv | 10.4161/cbt.23374 |
| format | Article |
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50
= approximately 10 µM) as well as multiple other cancer cell lines. Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic.</description><identifier>ISSN: 1538-4047</identifier><identifier>EISSN: 1555-8576</identifier><identifier>DOI: 10.4161/cbt.23374</identifier><identifier>PMID: 23298903</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>apoptosis ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors ; Cyclin-Dependent Kinase Inhibitor p21 - chemistry ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Humans ; Niacinamide - analogs & derivatives ; Niacinamide - chemistry ; Niacinamide - pharmacology ; p21 inhibitor ; Phenylurea Compounds - chemistry ; Phenylurea Compounds - pharmacology ; proliferation ; raf Kinases - antagonists & inhibitors ; Research Paper ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; sorafenib ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Cancer biology & therapy, 2013-03, Vol.14 (3), p.278-285</ispartof><rights>Copyright © 2013 Landes Bioscience 2013</rights><rights>Copyright © Landes Bioscience</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c486t-92694c099af270383bd6e75ff9807d54f9b04f7ec2e700ec8183f97b9b1e3f7a3</citedby><cites>FETCH-LOGICAL-c486t-92694c099af270383bd6e75ff9807d54f9b04f7ec2e700ec8183f97b9b1e3f7a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595311/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595311/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23298903$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wettersten, Hiromi I.</creatorcontrib><creatorcontrib>Hee Hwang, Sung</creatorcontrib><creatorcontrib>Li, Cuiwen</creatorcontrib><creatorcontrib>Shiu, Eunice Y.</creatorcontrib><creatorcontrib>Wecksler, Aaron T.</creatorcontrib><creatorcontrib>Hammock, Bruce D.</creatorcontrib><creatorcontrib>Weiss, Robert H.</creatorcontrib><title>A novel p21 attenuator which is structurally related to sorafenib</title><title>Cancer biology & therapy</title><addtitle>Cancer Biol Ther</addtitle><description>p21 is a member of the cyclin kinase inhibitor family of proteins and plays pivotal roles in cellular proliferation as well as in the regulation of apoptosis, and thus has diverse functions in diseases as varied as cancer and atherosclerosis. In light of its pleiotropic effects and potential clinical relevance, new methods of attenuation of p21 protein levels by selective inhibitors are therefore powerful tools to probe malignant, infectious and other diseases. Here we introduce a novel p21 attenuator, UC2288, which possesses consistent and relatively selective activity for p21. UC2288 was synthesized based on the chemical model of sorafenib, a multikinase inhibitor that also attenuates p21, but unlike sorafenib, UC2288 did not inhibit Raf kinases or alter p-ERK protein levels. UC2288 decreased p21 mRNA expression independently of p53, and attenuated p21 protein levels with minimal effect on p21 protein stability. In addition, UC2288 inhibits cell growth in the kidney cancer cell lines (GI
50
= approximately 10 µM) as well as multiple other cancer cell lines. Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic.</description><subject>apoptosis</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - chemistry</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Humans</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - chemistry</subject><subject>Niacinamide - pharmacology</subject><subject>p21 inhibitor</subject><subject>Phenylurea Compounds - chemistry</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>proliferation</subject><subject>raf Kinases - antagonists & inhibitors</subject><subject>Research Paper</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>sorafenib</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1538-4047</issn><issn>1555-8576</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNplkM1KLDEQhYMo_owufIFLlt5Fa9JJOp2NMMj1BwQ3ug7pdMWJZDpjklbm7W0dlSuuqqA-Th0-hI4pOeW0oWe2K6c1Y5JvoX0qhKhaIZvt9521FSdc7qGDnJ8IqWXdqF20V7NatYqwfTSf4yG-QMCrmmJTCgyjKTHh14W3C-wzziWNtozJhLDGCYIp0OMScY7JOBh8d4h2nAkZjj7nDD1c_ru_uK5u765uLua3leVtUyo1feaWKGVcLQlrWdc3IIVzqiWyF9ypjnAnwdYgCQHb0pY5JTvVUWBOGjZD55vc1dgtobcwlKmUXiW_NGmto_H652XwC_0YXzQTSjBKp4CTz4AUn0fIRS99thCCGSCOWVNGBWWimdrN0N8NalPMOYH7fkOJfleuJ-X6Q_nE_vm_1zf55XgC-Abwg4tpaV5jCr0uZh1icskM1mfNfue-AdQvjxg</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Wettersten, Hiromi I.</creator><creator>Hee Hwang, Sung</creator><creator>Li, Cuiwen</creator><creator>Shiu, Eunice Y.</creator><creator>Wecksler, Aaron T.</creator><creator>Hammock, Bruce D.</creator><creator>Weiss, Robert H.</creator><general>Taylor & Francis</general><general>Landes Bioscience</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><scope>5PM</scope></search><sort><creationdate>20130301</creationdate><title>A novel p21 attenuator which is structurally related to sorafenib</title><author>Wettersten, Hiromi I. ; Hee Hwang, Sung ; Li, Cuiwen ; Shiu, Eunice Y. ; Wecksler, Aaron T. ; Hammock, Bruce D. ; Weiss, Robert H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c486t-92694c099af270383bd6e75ff9807d54f9b04f7ec2e700ec8183f97b9b1e3f7a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>apoptosis</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - chemistry</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Humans</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - chemistry</topic><topic>Niacinamide - pharmacology</topic><topic>p21 inhibitor</topic><topic>Phenylurea Compounds - chemistry</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>proliferation</topic><topic>raf Kinases - antagonists & inhibitors</topic><topic>Research Paper</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>sorafenib</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wettersten, Hiromi I.</creatorcontrib><creatorcontrib>Hee Hwang, Sung</creatorcontrib><creatorcontrib>Li, Cuiwen</creatorcontrib><creatorcontrib>Shiu, Eunice Y.</creatorcontrib><creatorcontrib>Wecksler, Aaron T.</creatorcontrib><creatorcontrib>Hammock, Bruce D.</creatorcontrib><creatorcontrib>Weiss, Robert H.</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer biology & therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wettersten, Hiromi I.</au><au>Hee Hwang, Sung</au><au>Li, Cuiwen</au><au>Shiu, Eunice Y.</au><au>Wecksler, Aaron T.</au><au>Hammock, Bruce D.</au><au>Weiss, Robert H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel p21 attenuator which is structurally related to sorafenib</atitle><jtitle>Cancer biology & therapy</jtitle><addtitle>Cancer Biol Ther</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>14</volume><issue>3</issue><spage>278</spage><epage>285</epage><pages>278-285</pages><issn>1538-4047</issn><eissn>1555-8576</eissn><abstract>p21 is a member of the cyclin kinase inhibitor family of proteins and plays pivotal roles in cellular proliferation as well as in the regulation of apoptosis, and thus has diverse functions in diseases as varied as cancer and atherosclerosis. In light of its pleiotropic effects and potential clinical relevance, new methods of attenuation of p21 protein levels by selective inhibitors are therefore powerful tools to probe malignant, infectious and other diseases. Here we introduce a novel p21 attenuator, UC2288, which possesses consistent and relatively selective activity for p21. UC2288 was synthesized based on the chemical model of sorafenib, a multikinase inhibitor that also attenuates p21, but unlike sorafenib, UC2288 did not inhibit Raf kinases or alter p-ERK protein levels. UC2288 decreased p21 mRNA expression independently of p53, and attenuated p21 protein levels with minimal effect on p21 protein stability. In addition, UC2288 inhibits cell growth in the kidney cancer cell lines (GI
50
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | apoptosis Cell Line, Tumor Cell Proliferation - drug effects Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors Cyclin-Dependent Kinase Inhibitor p21 - chemistry Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Humans Niacinamide - analogs & derivatives Niacinamide - chemistry Niacinamide - pharmacology p21 inhibitor Phenylurea Compounds - chemistry Phenylurea Compounds - pharmacology proliferation raf Kinases - antagonists & inhibitors Research Paper RNA, Messenger - genetics RNA, Messenger - metabolism sorafenib Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | A novel p21 attenuator which is structurally related to sorafenib |
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