The discovery of potent small molecule cyclic urea activators of STING
STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery...
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| Veröffentlicht in: | European journal of medicinal chemistry 2022-02, Vol.229, p.114087-114087, Article 114087 |
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| container_title | European journal of medicinal chemistry |
| container_volume | 229 |
| creator | Basu, Sourav Middya, Sandip Banerjee, Monali Ghosh, Rajib Pryde, David C. Yadav, Dharmendra B. Shrivastava, Ritesh Surya, Arjun |
| description | STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery of 3,4-dihydroquinazolin-2(1H)-one based 6,6-bicyclic heterocyclic agonists of human STING that activate all known human variants of STING with high potency.
[Display omitted]
•Activation of STING is a highly promising approach in immunotherapy.•Optimised heterocyclic STING activators are based on a cyclic urea core.•The series potently activates all known human variants of STING and monkey STING.•An example potently induces release of inflammatory cytokines in PBMCs from monkeys.•An example has good drug-like properties and pharmacokinetics. |
| doi_str_mv | 10.1016/j.ejmech.2021.114087 |
| format | Article |
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[Display omitted]
•Activation of STING is a highly promising approach in immunotherapy.•Optimised heterocyclic STING activators are based on a cyclic urea core.•The series potently activates all known human variants of STING and monkey STING.•An example potently induces release of inflammatory cytokines in PBMCs from monkeys.•An example has good drug-like properties and pharmacokinetics.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2021.114087</identifier><identifier>PMID: 34998056</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; cGAS ; Cytosol - chemistry ; DNA - chemistry ; Haplorhini ; Humans ; Immune oncology ; Immunity, Innate - drug effects ; Innate immunity ; Interferon ; Male ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred BALB C ; Neoplasms - drug therapy ; Protein Binding ; Signal Transduction ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - pharmacology ; STING ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2022-02, Vol.229, p.114087-114087, Article 114087</ispartof><rights>2021 Elsevier Masson SAS</rights><rights>Copyright © 2021 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-5da66884f7ab5a88cdb9f940903da41179c65035de4f29ed47c76500c9ed9f333</citedby><cites>FETCH-LOGICAL-c362t-5da66884f7ab5a88cdb9f940903da41179c65035de4f29ed47c76500c9ed9f333</cites><orcidid>0000-0002-5767-030X ; 0000-0002-6080-7098</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523421009363$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34998056$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Basu, Sourav</creatorcontrib><creatorcontrib>Middya, Sandip</creatorcontrib><creatorcontrib>Banerjee, Monali</creatorcontrib><creatorcontrib>Ghosh, Rajib</creatorcontrib><creatorcontrib>Pryde, David C.</creatorcontrib><creatorcontrib>Yadav, Dharmendra B.</creatorcontrib><creatorcontrib>Shrivastava, Ritesh</creatorcontrib><creatorcontrib>Surya, Arjun</creatorcontrib><title>The discovery of potent small molecule cyclic urea activators of STING</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery of 3,4-dihydroquinazolin-2(1H)-one based 6,6-bicyclic heterocyclic agonists of human STING that activate all known human variants of STING with high potency.
[Display omitted]
•Activation of STING is a highly promising approach in immunotherapy.•Optimised heterocyclic STING activators are based on a cyclic urea core.•The series potently activates all known human variants of STING and monkey STING.•An example potently induces release of inflammatory cytokines in PBMCs from monkeys.•An example has good drug-like properties and pharmacokinetics.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>cGAS</subject><subject>Cytosol - chemistry</subject><subject>DNA - chemistry</subject><subject>Haplorhini</subject><subject>Humans</subject><subject>Immune oncology</subject><subject>Immunity, Innate - drug effects</subject><subject>Innate immunity</subject><subject>Interferon</subject><subject>Male</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Neoplasms - drug therapy</subject><subject>Protein Binding</subject><subject>Signal Transduction</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>STING</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1PwzAMQCMEYmPwDxDqkUtHvtomFyQ0sTFpggPjHGWJq7Vql5G0k_bvydTBkZNj6zm2H0L3BE8JJvlTPYW6BbOdUkzJlBCORXGBxqTIRcpoxi_RGFPK0owyPkI3IdQY4yzH-BqNGJdSxGSM5ustJLYKxh3AHxNXJnvXwa5LQqubJmldA6ZvIDFH01Qm6T3oRJuuOujO-XDiP9fL98Utuip1E-DuHCfoa_66nr2lq4_FcvaySg3LaZdmVue5ELws9CbTQhi7kaXkWGJmNSekkCbPMMss8JJKsLwwRSxgE9-yZIxN0OPw79677x5Cp9q4OzSN3oHrg6I5EZRRTHhE-YAa70LwUKq9r1rtj4pgdTKoajUYVCeDajAY2x7OE_pNC_av6VdZBJ4HAOKdhwq8CqaCnQFbeTCdsq76f8IPVayCaA</recordid><startdate>20220205</startdate><enddate>20220205</enddate><creator>Basu, Sourav</creator><creator>Middya, Sandip</creator><creator>Banerjee, Monali</creator><creator>Ghosh, Rajib</creator><creator>Pryde, David C.</creator><creator>Yadav, Dharmendra B.</creator><creator>Shrivastava, Ritesh</creator><creator>Surya, Arjun</creator><general>Elsevier Masson SAS</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><orcidid>https://orcid.org/0000-0002-5767-030X</orcidid><orcidid>https://orcid.org/0000-0002-6080-7098</orcidid></search><sort><creationdate>20220205</creationdate><title>The discovery of potent small molecule cyclic urea activators of STING</title><author>Basu, Sourav ; Middya, Sandip ; Banerjee, Monali ; Ghosh, Rajib ; Pryde, David C. ; Yadav, Dharmendra B. ; Shrivastava, Ritesh ; Surya, Arjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-5da66884f7ab5a88cdb9f940903da41179c65035de4f29ed47c76500c9ed9f333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>cGAS</topic><topic>Cytosol - chemistry</topic><topic>DNA - chemistry</topic><topic>Haplorhini</topic><topic>Humans</topic><topic>Immune oncology</topic><topic>Immunity, Innate - drug effects</topic><topic>Innate immunity</topic><topic>Interferon</topic><topic>Male</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Neoplasms - drug therapy</topic><topic>Protein Binding</topic><topic>Signal Transduction</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>STING</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Basu, Sourav</creatorcontrib><creatorcontrib>Middya, Sandip</creatorcontrib><creatorcontrib>Banerjee, Monali</creatorcontrib><creatorcontrib>Ghosh, Rajib</creatorcontrib><creatorcontrib>Pryde, David C.</creatorcontrib><creatorcontrib>Yadav, Dharmendra B.</creatorcontrib><creatorcontrib>Shrivastava, Ritesh</creatorcontrib><creatorcontrib>Surya, Arjun</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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Basu, Sourav</au><au>Middya, Sandip</au><au>Banerjee, Monali</au><au>Ghosh, Rajib</au><au>Pryde, David C.</au><au>Yadav, Dharmendra B.</au><au>Shrivastava, Ritesh</au><au>Surya, Arjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The discovery of potent small molecule cyclic urea activators of STING</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2022-02-05</date><risdate>2022</risdate><volume>229</volume><spage>114087</spage><epage>114087</epage><pages>114087-114087</pages><artnum>114087</artnum><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>STING mediates innate immune responses that are triggered by the presence of cytosolic DNA. Activation of STING to boost antigen recognition is a therapeutic modality that is currently being tested in cancer patients using nucleic-acid based macrocyclic STING ligands. We describe here the discovery of 3,4-dihydroquinazolin-2(1H)-one based 6,6-bicyclic heterocyclic agonists of human STING that activate all known human variants of STING with high potency.
[Display omitted]
•Activation of STING is a highly promising approach in immunotherapy.•Optimised heterocyclic STING activators are based on a cyclic urea core.•The series potently activates all known human variants of STING and monkey STING.•An example potently induces release of inflammatory cytokines in PBMCs from monkeys.•An example has good drug-like properties and pharmacokinetics.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>34998056</pmid><doi>10.1016/j.ejmech.2021.114087</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-5767-030X</orcidid><orcidid>https://orcid.org/0000-0002-6080-7098</orcidid></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2022-02, Vol.229, p.114087-114087, Article 114087 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis Bridged Bicyclo Compounds, Heterocyclic - pharmacology cGAS Cytosol - chemistry DNA - chemistry Haplorhini Humans Immune oncology Immunity, Innate - drug effects Innate immunity Interferon Male Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred BALB C Neoplasms - drug therapy Protein Binding Signal Transduction Small Molecule Libraries - chemical synthesis Small Molecule Libraries - pharmacology STING Structure-Activity Relationship |
| title | The discovery of potent small molecule cyclic urea activators of STING |
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