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Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP...
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| Published in: | Journal of medicinal chemistry 2004-08, Vol.47 (18), p.4417-4426 |
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| cites | cdi_FETCH-LOGICAL-a476t-4de3b8a979321074dc44b900098a9142e9e621b6267bf0a6a0725adb31a32e613 |
| container_end_page | 4426 |
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| container_title | Journal of medicinal chemistry |
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| creator | Oost, Thorsten K Sun, Chaohong Armstrong, Robert C Al-Assaad, Ali-Samer Betz, Stephen F Deckwerth, Thomas L Ding, Hong Elmore, Steven W Meadows, Robert P Olejniczak, Edward T Oleksijew, Andrew Oltersdorf, Tilman Rosenberg, Saul H Shoemaker, Alexander R Tomaselli, Kevin J Zou, Hua Fesik, Stephen W |
| description | Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP−BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP. |
| doi_str_mv | 10.1021/jm040037k |
| format | article |
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On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP−BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm040037k</identifier><identifier>PMID: 15317454</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Baculovirus ; Binding Sites ; Biological and medical sciences ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; Carrier Proteins - chemistry ; Carrier Proteins - therapeutic use ; Caspases - drug effects ; Cell Division - drug effects ; Cell Line, Tumor ; General aspects ; Humans ; Intracellular Signaling Peptides and Proteins ; Ligands ; Medical sciences ; Mice ; Mitochondrial Proteins - chemistry ; Mitochondrial Proteins - therapeutic use ; Peptide Fragments - chemistry ; Peptide Fragments - therapeutic use ; Pharmacology. Drug treatments ; Protein Structure, Tertiary ; Proteins - antagonists & inhibitors ; Structure-Activity Relationship ; Transplantation, Heterologous ; X-Linked Inhibitor of Apoptosis Protein</subject><ispartof>Journal of medicinal chemistry, 2004-08, Vol.47 (18), p.4417-4426</ispartof><rights>Copyright © 2004 American Chemical Society</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a476t-4de3b8a979321074dc44b900098a9142e9e621b6267bf0a6a0725adb31a32e613</citedby><cites>FETCH-LOGICAL-a476t-4de3b8a979321074dc44b900098a9142e9e621b6267bf0a6a0725adb31a32e613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16040963$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15317454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oost, Thorsten K</creatorcontrib><creatorcontrib>Sun, Chaohong</creatorcontrib><creatorcontrib>Armstrong, Robert C</creatorcontrib><creatorcontrib>Al-Assaad, Ali-Samer</creatorcontrib><creatorcontrib>Betz, Stephen F</creatorcontrib><creatorcontrib>Deckwerth, Thomas L</creatorcontrib><creatorcontrib>Ding, Hong</creatorcontrib><creatorcontrib>Elmore, Steven W</creatorcontrib><creatorcontrib>Meadows, Robert P</creatorcontrib><creatorcontrib>Olejniczak, Edward T</creatorcontrib><creatorcontrib>Oleksijew, Andrew</creatorcontrib><creatorcontrib>Oltersdorf, Tilman</creatorcontrib><creatorcontrib>Rosenberg, Saul H</creatorcontrib><creatorcontrib>Shoemaker, Alexander R</creatorcontrib><creatorcontrib>Tomaselli, Kevin J</creatorcontrib><creatorcontrib>Zou, Hua</creatorcontrib><creatorcontrib>Fesik, Stephen W</creatorcontrib><title>Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP−BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Baculovirus</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - pathology</subject><subject>Carrier Proteins - chemistry</subject><subject>Carrier Proteins - therapeutic use</subject><subject>Caspases - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Cell Line, Tumor</subject><subject>General aspects</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mitochondrial Proteins - chemistry</subject><subject>Mitochondrial Proteins - therapeutic use</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - therapeutic use</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Transplantation, Heterologous</subject><subject>X-Linked Inhibitor of Apoptosis Protein</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqF0MtKAzEUBuAgitbqwheQ2Si4GM1tksmy1CsULFjBjYQz04xO7Uxqkop9e1Nb2o3gKnDynZ_kR-iE4EuCKbmaNJhjzOTHDuqQjOKU55jvog7GlKZUUHaADr2f4GgIZfvogGSMSJ7xDnq9rn1pv4xbJLZKhjaYNiS9NsCbbWsf_HIa3s1yVMPMzoINdZkMXYR1m7w89IZJZd0vGTkDoVnux50-tKVxR2ivgqk3x-uzi55vb0b9-3TwePfQ7w1S4FKElI8NK3JQUjFKsOTjkvNCxeeqOCScGmUEJYWgQhYVBgFY0gzGBSPAqBGEddH5Knfm7Ofc-KCb-C0znUJr7NxrIaSK2fm_kCgu84xlEV6sYOms985UeubqBtxCE6yXpetN6dGerkPnRWPGW7luOYKzNQBfwrRysZzab52ISUqw6NKVi82b7809uA8tJJOZHg2fdD9_Ufc0e9KDbS6UXk_s3LWx5D8e-ANNBqLS</recordid><startdate>20040826</startdate><enddate>20040826</enddate><creator>Oost, Thorsten K</creator><creator>Sun, Chaohong</creator><creator>Armstrong, Robert C</creator><creator>Al-Assaad, Ali-Samer</creator><creator>Betz, Stephen F</creator><creator>Deckwerth, Thomas L</creator><creator>Ding, Hong</creator><creator>Elmore, Steven W</creator><creator>Meadows, Robert P</creator><creator>Olejniczak, Edward T</creator><creator>Oleksijew, Andrew</creator><creator>Oltersdorf, Tilman</creator><creator>Rosenberg, Saul H</creator><creator>Shoemaker, Alexander R</creator><creator>Tomaselli, Kevin J</creator><creator>Zou, Hua</creator><creator>Fesik, Stephen W</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20040826</creationdate><title>Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer</title><author>Oost, Thorsten K ; Sun, Chaohong ; Armstrong, Robert C ; Al-Assaad, Ali-Samer ; Betz, Stephen F ; Deckwerth, Thomas L ; Ding, Hong ; Elmore, Steven W ; Meadows, Robert P ; Olejniczak, Edward T ; Oleksijew, Andrew ; Oltersdorf, Tilman ; Rosenberg, Saul H ; Shoemaker, Alexander R ; Tomaselli, Kevin J ; Zou, Hua ; Fesik, Stephen W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a476t-4de3b8a979321074dc44b900098a9142e9e621b6267bf0a6a0725adb31a32e613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Baculovirus</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - pathology</topic><topic>Carrier Proteins - chemistry</topic><topic>Carrier Proteins - therapeutic use</topic><topic>Caspases - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Cell Line, Tumor</topic><topic>General aspects</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mitochondrial Proteins - chemistry</topic><topic>Mitochondrial Proteins - therapeutic use</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - therapeutic use</topic><topic>Pharmacology. 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Med. Chem</addtitle><date>2004-08-26</date><risdate>2004</risdate><volume>47</volume><issue>18</issue><spage>4417</spage><epage>4426</epage><pages>4417-4426</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><notes>istex:4F996124C3DF0CF9DE38569E86A28229A5C675E8</notes><notes>ark:/67375/TPS-C8X9H25S-L</notes><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><abstract>Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP−BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>15317454</pmid><doi>10.1021/jm040037k</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2004-08, Vol.47 (18), p.4417-4426 |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Antineoplastic agents Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Baculovirus Binding Sites Biological and medical sciences Breast Neoplasms - drug therapy Breast Neoplasms - pathology Carrier Proteins - chemistry Carrier Proteins - therapeutic use Caspases - drug effects Cell Division - drug effects Cell Line, Tumor General aspects Humans Intracellular Signaling Peptides and Proteins Ligands Medical sciences Mice Mitochondrial Proteins - chemistry Mitochondrial Proteins - therapeutic use Peptide Fragments - chemistry Peptide Fragments - therapeutic use Pharmacology. Drug treatments Protein Structure, Tertiary Proteins - antagonists & inhibitors Structure-Activity Relationship Transplantation, Heterologous X-Linked Inhibitor of Apoptosis Protein |
| title | Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer |
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