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Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor
Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface mark...
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| Published in: | Angewandte Chemie International Edition 2016-03, Vol.55 (11), p.3642-3646 |
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| Main Authors: | , , , , , , , , |
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| cites | cdi_FETCH-LOGICAL-c7776-3f521a0a2e616c26153c5884a2ddf662c179f13569a840cf6df792604464db6d3 |
| container_end_page | 3646 |
| container_issue | 11 |
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| container_title | Angewandte Chemie International Edition |
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| creator | Rullo, Anthony F. Fitzgerald, Kelly J. Muthusamy, Viswanathan Liu, Min Yuan, Cai Huang, Mingdong Kim, Minsup Cho, Art E. Spiegel, David A. |
| description | Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface marker, and facilitating the immune‐mediated destruction of cancer cells. A co‐crystal structure of the ARM‐U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non‐peptide ligand. Finally, we demonstrated that ARM‐U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard‐of‐care agent doxorubicin. This work underscores the promise of antibody‐recruiting molecules as immunotherapeutics for treating cancer.
Marked for death: A small‐molecule immunotherapeutic strategy involves the selective tagging of cancer cells for immune‐cell recognition and targeted destruction. This approach holds tremendous promise in guiding the development of selective treatments against highly aggressive metastatic cancers with potentially few side effects. |
| doi_str_mv | 10.1002/anie.201510866 |
| format | article |
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Marked for death: A small‐molecule immunotherapeutic strategy involves the selective tagging of cancer cells for immune‐cell recognition and targeted destruction. This approach holds tremendous promise in guiding the development of selective treatments against highly aggressive metastatic cancers with potentially few side effects.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.201510866</identifier><identifier>PMID: 26879524</identifier><identifier>CODEN: ACIEAY</identifier><language>eng</language><publisher>Germany: Blackwell Publishing Ltd</publisher><subject>Antibodies - immunology ; antitumor agents ; Cancer ; cell recognition ; Cell surface ; Crystal structure ; Crystallography, X-Ray ; Destruction ; Doxorubicin ; drug design ; Engineering ; Humans ; Immune response ; Immune system ; immunology ; medicinal chemistry ; Metastases ; Metastasis ; Neoplasm Metastasis - immunology ; Neoplasms - pathology ; Reengineering ; Surface markers ; U-Plasminogen activator ; Urokinase ; Urokinase-Type Plasminogen Activator - metabolism ; Weight loss</subject><ispartof>Angewandte Chemie International Edition, 2016-03, Vol.55 (11), p.3642-3646</ispartof><rights>2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c7776-3f521a0a2e616c26153c5884a2ddf662c179f13569a840cf6df792604464db6d3</citedby><cites>FETCH-LOGICAL-c7776-3f521a0a2e616c26153c5884a2ddf662c179f13569a840cf6df792604464db6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26879524$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rullo, Anthony F.</creatorcontrib><creatorcontrib>Fitzgerald, Kelly J.</creatorcontrib><creatorcontrib>Muthusamy, Viswanathan</creatorcontrib><creatorcontrib>Liu, Min</creatorcontrib><creatorcontrib>Yuan, Cai</creatorcontrib><creatorcontrib>Huang, Mingdong</creatorcontrib><creatorcontrib>Kim, Minsup</creatorcontrib><creatorcontrib>Cho, Art E.</creatorcontrib><creatorcontrib>Spiegel, David A.</creatorcontrib><title>Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor</title><title>Angewandte Chemie International Edition</title><addtitle>Angew. Chem. Int. Ed</addtitle><description>Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface marker, and facilitating the immune‐mediated destruction of cancer cells. A co‐crystal structure of the ARM‐U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non‐peptide ligand. Finally, we demonstrated that ARM‐U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard‐of‐care agent doxorubicin. This work underscores the promise of antibody‐recruiting molecules as immunotherapeutics for treating cancer.
Marked for death: A small‐molecule immunotherapeutic strategy involves the selective tagging of cancer cells for immune‐cell recognition and targeted destruction. This approach holds tremendous promise in guiding the development of selective treatments against highly aggressive metastatic cancers with potentially few side effects.</description><subject>Antibodies - immunology</subject><subject>antitumor agents</subject><subject>Cancer</subject><subject>cell recognition</subject><subject>Cell surface</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Destruction</subject><subject>Doxorubicin</subject><subject>drug design</subject><subject>Engineering</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>immunology</subject><subject>medicinal chemistry</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Neoplasm Metastasis - immunology</subject><subject>Neoplasms - pathology</subject><subject>Reengineering</subject><subject>Surface markers</subject><subject>U-Plasminogen activator</subject><subject>Urokinase</subject><subject>Urokinase-Type Plasminogen Activator - metabolism</subject><subject>Weight loss</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNqFkc9v0zAYhiMEYmNw5YgiceGS4h_JZ4cDUlWNUbQO1G3a0XKdL5231O5sB-iB_51U3arBAU625Od95Fdvlr2mZEQJYe-1szhihFaUSIAn2SGtGC24EPzpcC85L4Ss6EH2IsabgZeSwPPsgIEUdcXKw-zXHAt0S-sQg3XLPF1jPl2teof5HOPau4h58vkMk45JJ2vyiXYGw4d87JJd-GZTzNGE3qZt-nyluy6f-Q5N32HML3RYYnrwXgZ_a52OW7XBdfLhZfas1V3EV_fnUXb56fhi8rk4_XoynYxPCyOEgIK3QylNNEOgYBjQiptKylKzpmkBmKGibimvoNayJKaFphU1A1KWUDYLaPhR9nHnXfeLFTYGXQq6U-tgVzpslNdW_fni7LVa-u-qqmrBCRsE7-4Fwd_1GJNa2Wiw67RD30dFBdS1pATogL79C73xfXBDPUVrAgBEMvJPSoAESpmEgRrtKBN8jAHb_ZcpUdv91XZ_td9_CLx5XHSPPww-APUO-GE73PxHp8Zn0-PH8mKXtTHhz31Wh1sFgotKXZ2dqMmVYN_o7Is6578BVwjMUA</recordid><startdate>20160307</startdate><enddate>20160307</enddate><creator>Rullo, Anthony F.</creator><creator>Fitzgerald, Kelly J.</creator><creator>Muthusamy, Viswanathan</creator><creator>Liu, Min</creator><creator>Yuan, Cai</creator><creator>Huang, Mingdong</creator><creator>Kim, Minsup</creator><creator>Cho, Art E.</creator><creator>Spiegel, David A.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7TM</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160307</creationdate><title>Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor</title><author>Rullo, Anthony F. ; Fitzgerald, Kelly J. ; Muthusamy, Viswanathan ; Liu, Min ; Yuan, Cai ; Huang, Mingdong ; Kim, Minsup ; Cho, Art E. ; Spiegel, David A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c7776-3f521a0a2e616c26153c5884a2ddf662c179f13569a840cf6df792604464db6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Antibodies - immunology</topic><topic>antitumor agents</topic><topic>Cancer</topic><topic>cell recognition</topic><topic>Cell surface</topic><topic>Crystal structure</topic><topic>Crystallography, X-Ray</topic><topic>Destruction</topic><topic>Doxorubicin</topic><topic>drug design</topic><topic>Engineering</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>immunology</topic><topic>medicinal chemistry</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Neoplasm Metastasis - immunology</topic><topic>Neoplasms - pathology</topic><topic>Reengineering</topic><topic>Surface markers</topic><topic>U-Plasminogen activator</topic><topic>Urokinase</topic><topic>Urokinase-Type Plasminogen Activator - metabolism</topic><topic>Weight loss</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rullo, Anthony F.</creatorcontrib><creatorcontrib>Fitzgerald, Kelly J.</creatorcontrib><creatorcontrib>Muthusamy, Viswanathan</creatorcontrib><creatorcontrib>Liu, Min</creatorcontrib><creatorcontrib>Yuan, Cai</creatorcontrib><creatorcontrib>Huang, Mingdong</creatorcontrib><creatorcontrib>Kim, Minsup</creatorcontrib><creatorcontrib>Cho, Art E.</creatorcontrib><creatorcontrib>Spiegel, David A.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rullo, Anthony F.</au><au>Fitzgerald, Kelly J.</au><au>Muthusamy, Viswanathan</au><au>Liu, Min</au><au>Yuan, Cai</au><au>Huang, Mingdong</au><au>Kim, Minsup</au><au>Cho, Art E.</au><au>Spiegel, David A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew. Chem. Int. Ed</addtitle><date>2016-03-07</date><risdate>2016</risdate><volume>55</volume><issue>11</issue><spage>3642</spage><epage>3646</epage><pages>3642-3646</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><coden>ACIEAY</coden><abstract>Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface marker, and facilitating the immune‐mediated destruction of cancer cells. A co‐crystal structure of the ARM‐U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non‐peptide ligand. Finally, we demonstrated that ARM‐U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard‐of‐care agent doxorubicin. This work underscores the promise of antibody‐recruiting molecules as immunotherapeutics for treating cancer.
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| identifier | ISSN: 1433-7851 |
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| subjects | Antibodies - immunology antitumor agents Cancer cell recognition Cell surface Crystal structure Crystallography, X-Ray Destruction Doxorubicin drug design Engineering Humans Immune response Immune system immunology medicinal chemistry Metastases Metastasis Neoplasm Metastasis - immunology Neoplasms - pathology Reengineering Surface markers U-Plasminogen activator Urokinase Urokinase-Type Plasminogen Activator - metabolism Weight loss |
| title | Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor |
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