Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases
Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjö...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2023-08, Vol.14 (8), p.1054-1062 |
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| creator | Alper, Phil Betschart, Claudia André, Cédric Boulay, Thomas Cheng, Dai Deane, Jonathan Faller, Michael Feifel, Roland Glatthar, Ralf Han, Dong Hemmig, Rene Jiang, Tao Knoepfel, Thomas Maginnis, Jillian Mutnick, Daniel Pei, Wei Ruzzante, Giulia Syka, Peter Zhang, Guobao Zhang, Yi Zink, Florence Zipfel, Géraldine Hawtin, Stuart Junt, Tobias Michellys, Pierre-Yves |
| description | Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren’s syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren’s syndrome and mixed connective tissue disease. |
| doi_str_mv | 10.1021/acsmedchemlett.3c00136 |
| format | Article |
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Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren’s syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren’s syndrome and mixed connective tissue disease.</description><identifier>ISSN: 1948-5875</identifier><identifier>EISSN: 1948-5875</identifier><identifier>DOI: 10.1021/acsmedchemlett.3c00136</identifier><identifier>PMID: 37583811</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><ispartof>ACS medicinal chemistry letters, 2023-08, Vol.14 (8), p.1054-1062</ispartof><rights>2023 American Chemical Society</rights><rights>2023 American Chemical Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a354t-9798d1d93f54bd483296741e353c435c87544eeb642f8f90c8b3c7b08feaa75e3</citedby><cites>FETCH-LOGICAL-a354t-9798d1d93f54bd483296741e353c435c87544eeb642f8f90c8b3c7b08feaa75e3</cites><orcidid>0000-0002-4115-0633 ; 0000-0002-7770-6605 ; 0000-0002-1675-6297</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/acsmedchemlett.3c00136$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00136$$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/37583811$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alper, Phil</creatorcontrib><creatorcontrib>Betschart, Claudia</creatorcontrib><creatorcontrib>André, Cédric</creatorcontrib><creatorcontrib>Boulay, Thomas</creatorcontrib><creatorcontrib>Cheng, Dai</creatorcontrib><creatorcontrib>Deane, Jonathan</creatorcontrib><creatorcontrib>Faller, Michael</creatorcontrib><creatorcontrib>Feifel, Roland</creatorcontrib><creatorcontrib>Glatthar, Ralf</creatorcontrib><creatorcontrib>Han, Dong</creatorcontrib><creatorcontrib>Hemmig, Rene</creatorcontrib><creatorcontrib>Jiang, Tao</creatorcontrib><creatorcontrib>Knoepfel, Thomas</creatorcontrib><creatorcontrib>Maginnis, Jillian</creatorcontrib><creatorcontrib>Mutnick, Daniel</creatorcontrib><creatorcontrib>Pei, Wei</creatorcontrib><creatorcontrib>Ruzzante, Giulia</creatorcontrib><creatorcontrib>Syka, Peter</creatorcontrib><creatorcontrib>Zhang, Guobao</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Zink, Florence</creatorcontrib><creatorcontrib>Zipfel, Géraldine</creatorcontrib><creatorcontrib>Hawtin, Stuart</creatorcontrib><creatorcontrib>Junt, Tobias</creatorcontrib><creatorcontrib>Michellys, Pierre-Yves</creatorcontrib><title>Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases</title><title>ACS medicinal chemistry letters</title><addtitle>ACS Med. Chem. Lett</addtitle><description>Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren’s syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren’s syndrome and mixed connective tissue disease.</description><issn>1948-5875</issn><issn>1948-5875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFkMtOwzAQRS0EouXxC5WXbNrasR07y6o8ilSEBAWWkeNMaKomLraD1L_HVQuCFasZac7cmXsRGlAyoiShY218A6VZQrOGEEbMEEJZeoT6NONqKJQUx7_6HjrzfkVImklJTlGPSaGYorSP3q5rb-wnuC22FQ5LwIv5kxwrPGmDfrdt7QN-mL0ySXBlHV440KGBNuzo560P0NQGT7pg66bpWsBRDrQHf4FOKr32cHmo5-jl9mYxnQ3nj3f308l8qJngYZjJTJW0zFgleFFyxZIslZwCE8xwJkz8nXOAIuVJpaqMGFUwIwuiKtBaCmDn6Gqvu3H2owMf8iYagvVat2A7nydKUCVJSmVE0z1qnPXeQZVvXN1ot80pyXeh5n9DzQ-hxsXB4UZXxPnP2neKEUj2QBTIV7ZzbbT8n-oXspaHdw</recordid><startdate>20230810</startdate><enddate>20230810</enddate><creator>Alper, Phil</creator><creator>Betschart, Claudia</creator><creator>André, Cédric</creator><creator>Boulay, Thomas</creator><creator>Cheng, Dai</creator><creator>Deane, Jonathan</creator><creator>Faller, Michael</creator><creator>Feifel, Roland</creator><creator>Glatthar, Ralf</creator><creator>Han, Dong</creator><creator>Hemmig, Rene</creator><creator>Jiang, Tao</creator><creator>Knoepfel, Thomas</creator><creator>Maginnis, Jillian</creator><creator>Mutnick, Daniel</creator><creator>Pei, Wei</creator><creator>Ruzzante, Giulia</creator><creator>Syka, Peter</creator><creator>Zhang, Guobao</creator><creator>Zhang, Yi</creator><creator>Zink, Florence</creator><creator>Zipfel, Géraldine</creator><creator>Hawtin, Stuart</creator><creator>Junt, Tobias</creator><creator>Michellys, Pierre-Yves</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4115-0633</orcidid><orcidid>https://orcid.org/0000-0002-7770-6605</orcidid><orcidid>https://orcid.org/0000-0002-1675-6297</orcidid></search><sort><creationdate>20230810</creationdate><title>Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases</title><author>Alper, Phil ; 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Chem. Lett</addtitle><date>2023-08-10</date><risdate>2023</risdate><volume>14</volume><issue>8</issue><spage>1054</spage><epage>1062</epage><pages>1054-1062</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><abstract>Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren’s syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren’s syndrome and mixed connective tissue disease.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>37583811</pmid><doi>10.1021/acsmedchemlett.3c00136</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-4115-0633</orcidid><orcidid>https://orcid.org/0000-0002-7770-6605</orcidid><orcidid>https://orcid.org/0000-0002-1675-6297</orcidid></addata></record> |
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| title | Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases |
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