Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors
The C–C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-08, Vol.63 (15), p.8584-8607 |
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| creator | Robles, Omar Jackson, Jeffrey J Marshall, Lisa Talay, Oezcan Chian, David Cutler, Gene Diokno, Raymond Hu, Dennis X Jacobson, Scott Karbarz, Emily Kassner, Paul D Ketcham, John M McKinnell, Jenny Meleza, Cesar Reilly, Maureen K Riegler, Erin Shunatona, Hunter P Wadsworth, Angela Younai, Ashkaan Brockstedt, Dirk G Wustrow, David J Zibinsky, Mikhail |
| description | The C–C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein. |
| doi_str_mv | 10.1021/acs.jmedchem.0c00988 |
| format | Article |
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Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c00988</identifier><identifier>PMID: 32667798</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Azetidines - chemistry ; Azetidines - pharmacokinetics ; Azetidines - pharmacology ; Azetidines - therapeutic use ; Cell Line, Tumor ; Dogs ; Humans ; Macaca fascicularis ; Neoplasms - drug therapy ; Neoplasms - immunology ; Piperidines - chemistry ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Piperidines - therapeutic use ; Receptors, CCR4 - antagonists & inhibitors ; Receptors, CCR4 - immunology ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology</subject><ispartof>Journal of medicinal chemistry, 2020-08, Vol.63 (15), p.8584-8607</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-9cbd241c9c461ebed1dfc9c3320f021929d20031fdd015baa602cd834259baca3</citedby><cites>FETCH-LOGICAL-a348t-9cbd241c9c461ebed1dfc9c3320f021929d20031fdd015baa602cd834259baca3</cites><orcidid>0000-0002-7219-5279</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c00988$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00988$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32667798$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Robles, Omar</creatorcontrib><creatorcontrib>Jackson, Jeffrey J</creatorcontrib><creatorcontrib>Marshall, Lisa</creatorcontrib><creatorcontrib>Talay, Oezcan</creatorcontrib><creatorcontrib>Chian, David</creatorcontrib><creatorcontrib>Cutler, Gene</creatorcontrib><creatorcontrib>Diokno, Raymond</creatorcontrib><creatorcontrib>Hu, Dennis X</creatorcontrib><creatorcontrib>Jacobson, Scott</creatorcontrib><creatorcontrib>Karbarz, Emily</creatorcontrib><creatorcontrib>Kassner, Paul D</creatorcontrib><creatorcontrib>Ketcham, John M</creatorcontrib><creatorcontrib>McKinnell, Jenny</creatorcontrib><creatorcontrib>Meleza, Cesar</creatorcontrib><creatorcontrib>Reilly, Maureen K</creatorcontrib><creatorcontrib>Riegler, Erin</creatorcontrib><creatorcontrib>Shunatona, Hunter P</creatorcontrib><creatorcontrib>Wadsworth, Angela</creatorcontrib><creatorcontrib>Younai, Ashkaan</creatorcontrib><creatorcontrib>Brockstedt, Dirk G</creatorcontrib><creatorcontrib>Wustrow, David J</creatorcontrib><creatorcontrib>Zibinsky, Mikhail</creatorcontrib><title>Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The C–C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Azetidines - chemistry</subject><subject>Azetidines - pharmacokinetics</subject><subject>Azetidines - pharmacology</subject><subject>Azetidines - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Dogs</subject><subject>Humans</subject><subject>Macaca fascicularis</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - immunology</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - pharmacology</subject><subject>Piperidines - therapeutic use</subject><subject>Receptors, CCR4 - antagonists & inhibitors</subject><subject>Receptors, CCR4 - immunology</subject><subject>T-Lymphocytes, Regulatory - drug effects</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN1O4zAQha0Vq6Ww-wYr5BdIGdtpSC6riD8JAQL2OnLsSTuQ2FHsguBleFUSSrncq_k750jzMfZXwFyAFMfahPljh9assZuDASjy_AebiYWEJM0h3WMzACkTmUm1zw5CeAQAJaT6xfaVzLKTkyKfsfdr_4wtv6UeB7LkXttk-YZxajFwHfitj-gi187ye2zRRHpGXpZ3KV-6qFfeUYiBn7ZkKE4ripvOD_wOQ-9dwClC83tyqxb5crWLIsdL39XkdCTv-AvFNS_XaJ56T6Pk0q2ppuiH8Jv9bHQb8M9XPWT_zk4fyovk6ub8slxeJVqleUwKU1uZClOYNBNYoxW2GQelJDQjrEIWVk7fN9aCWNRaZyCNzVUqF0WtjVaHLN3mmsGHMGBT9QN1enitBFQT72rkXe14V1-8R9vR1tZv6vH2bdoBHgWwFXza_WZw4xf_z_wAtc2TDw</recordid><startdate>20200813</startdate><enddate>20200813</enddate><creator>Robles, Omar</creator><creator>Jackson, Jeffrey J</creator><creator>Marshall, Lisa</creator><creator>Talay, Oezcan</creator><creator>Chian, David</creator><creator>Cutler, Gene</creator><creator>Diokno, Raymond</creator><creator>Hu, Dennis X</creator><creator>Jacobson, Scott</creator><creator>Karbarz, Emily</creator><creator>Kassner, Paul D</creator><creator>Ketcham, John M</creator><creator>McKinnell, Jenny</creator><creator>Meleza, Cesar</creator><creator>Reilly, Maureen K</creator><creator>Riegler, Erin</creator><creator>Shunatona, Hunter P</creator><creator>Wadsworth, Angela</creator><creator>Younai, Ashkaan</creator><creator>Brockstedt, Dirk G</creator><creator>Wustrow, David J</creator><creator>Zibinsky, Mikhail</creator><general>American Chemical Society</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><orcidid>https://orcid.org/0000-0002-7219-5279</orcidid></search><sort><creationdate>20200813</creationdate><title>Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors</title><author>Robles, Omar ; Jackson, Jeffrey J ; Marshall, Lisa ; Talay, Oezcan ; Chian, David ; Cutler, Gene ; Diokno, Raymond ; Hu, Dennis X ; Jacobson, Scott ; Karbarz, Emily ; Kassner, Paul D ; Ketcham, John M ; McKinnell, Jenny ; Meleza, Cesar ; Reilly, Maureen K ; Riegler, Erin ; Shunatona, Hunter P ; Wadsworth, Angela ; Younai, Ashkaan ; Brockstedt, Dirk G ; Wustrow, David J ; Zibinsky, Mikhail</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-9cbd241c9c461ebed1dfc9c3320f021929d20031fdd015baa602cd834259baca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Azetidines - chemistry</topic><topic>Azetidines - pharmacokinetics</topic><topic>Azetidines - pharmacology</topic><topic>Azetidines - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Dogs</topic><topic>Humans</topic><topic>Macaca fascicularis</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - immunology</topic><topic>Piperidines - chemistry</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - pharmacology</topic><topic>Piperidines - therapeutic use</topic><topic>Receptors, CCR4 - antagonists & inhibitors</topic><topic>Receptors, CCR4 - immunology</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Robles, Omar</creatorcontrib><creatorcontrib>Jackson, Jeffrey J</creatorcontrib><creatorcontrib>Marshall, Lisa</creatorcontrib><creatorcontrib>Talay, Oezcan</creatorcontrib><creatorcontrib>Chian, David</creatorcontrib><creatorcontrib>Cutler, Gene</creatorcontrib><creatorcontrib>Diokno, Raymond</creatorcontrib><creatorcontrib>Hu, Dennis X</creatorcontrib><creatorcontrib>Jacobson, Scott</creatorcontrib><creatorcontrib>Karbarz, Emily</creatorcontrib><creatorcontrib>Kassner, Paul D</creatorcontrib><creatorcontrib>Ketcham, John M</creatorcontrib><creatorcontrib>McKinnell, Jenny</creatorcontrib><creatorcontrib>Meleza, Cesar</creatorcontrib><creatorcontrib>Reilly, Maureen K</creatorcontrib><creatorcontrib>Riegler, Erin</creatorcontrib><creatorcontrib>Shunatona, Hunter P</creatorcontrib><creatorcontrib>Wadsworth, Angela</creatorcontrib><creatorcontrib>Younai, Ashkaan</creatorcontrib><creatorcontrib>Brockstedt, Dirk G</creatorcontrib><creatorcontrib>Wustrow, David J</creatorcontrib><creatorcontrib>Zibinsky, Mikhail</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robles, Omar</au><au>Jackson, Jeffrey J</au><au>Marshall, Lisa</au><au>Talay, Oezcan</au><au>Chian, David</au><au>Cutler, Gene</au><au>Diokno, Raymond</au><au>Hu, Dennis X</au><au>Jacobson, Scott</au><au>Karbarz, Emily</au><au>Kassner, Paul D</au><au>Ketcham, John M</au><au>McKinnell, Jenny</au><au>Meleza, Cesar</au><au>Reilly, Maureen K</au><au>Riegler, Erin</au><au>Shunatona, Hunter P</au><au>Wadsworth, Angela</au><au>Younai, Ashkaan</au><au>Brockstedt, Dirk G</au><au>Wustrow, David J</au><au>Zibinsky, Mikhail</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-08-13</date><risdate>2020</risdate><volume>63</volume><issue>15</issue><spage>8584</spage><epage>8607</epage><pages>8584-8607</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The C–C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32667798</pmid><doi>10.1021/acs.jmedchem.0c00988</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-7219-5279</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2020-08, Vol.63 (15), p.8584-8607 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Azetidines - chemistry Azetidines - pharmacokinetics Azetidines - pharmacology Azetidines - therapeutic use Cell Line, Tumor Dogs Humans Macaca fascicularis Neoplasms - drug therapy Neoplasms - immunology Piperidines - chemistry Piperidines - pharmacokinetics Piperidines - pharmacology Piperidines - therapeutic use Receptors, CCR4 - antagonists & inhibitors Receptors, CCR4 - immunology T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology |
| title | Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors |
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