Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L‑783277
We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1–6), ALK1 is most s...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-02, Vol.60 (4), p.1495-1508 |
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| container_title | Journal of medicinal chemistry |
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| creator | Cho, Hanna Sengupta, Sandip Jeon, Sean S. H Hur, Wooyoung Choi, Hwan Geun Seo, Hong-Seog Lee, Byung Joo Kim, Jeong Hun Chung, Minhwan Jeon, Noo Li Kim, Nam Doo Sim, Taebo |
| description | We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1–6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4′ hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, 1 is the first selective ALK1 inhibitor. Furthermore, compound 1 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that 1 could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1. |
| doi_str_mv | 10.1021/acs.jmedchem.6b01679 |
| format | Article |
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H ; Hur, Wooyoung ; Choi, Hwan Geun ; Seo, Hong-Seog ; Lee, Byung Joo ; Kim, Jeong Hun ; Chung, Minhwan ; Jeon, Noo Li ; Kim, Nam Doo ; Sim, Taebo</creator><creatorcontrib>Cho, Hanna ; Sengupta, Sandip ; Jeon, Sean S. H ; Hur, Wooyoung ; Choi, Hwan Geun ; Seo, Hong-Seog ; Lee, Byung Joo ; Kim, Jeong Hun ; Chung, Minhwan ; Jeon, Noo Li ; Kim, Nam Doo ; Sim, Taebo</creatorcontrib><description>We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1–6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4′ hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, 1 is the first selective ALK1 inhibitor. Furthermore, compound 1 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that 1 could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b01679</identifier><identifier>PMID: 28103025</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Activin Receptors, Type II - antagonists & inhibitors ; Activin Receptors, Type II - chemistry ; Activin Receptors, Type II - metabolism ; Amino Acid Sequence ; Angiogenesis Inducing Agents - chemistry ; Angiogenesis Inducing Agents - pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; Lactones - chemistry ; Lactones - pharmacology ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Resorcinols - chemistry ; Resorcinols - pharmacology ; Sequence Alignment ; Signal Transduction - drug effects ; Smad Proteins - metabolism</subject><ispartof>Journal of medicinal chemistry, 2017-02, Vol.60 (4), p.1495-1508</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-ca876bc9ea77cfc0e779f57edd571fbf465b23e084a3c75ae3a39fdebd3cff993</citedby><cites>FETCH-LOGICAL-a348t-ca876bc9ea77cfc0e779f57edd571fbf465b23e084a3c75ae3a39fdebd3cff993</cites><orcidid>0000-0003-3015-2059</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.6b01679$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01679$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28103025$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cho, Hanna</creatorcontrib><creatorcontrib>Sengupta, Sandip</creatorcontrib><creatorcontrib>Jeon, Sean S. 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Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4′ hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, 1 is the first selective ALK1 inhibitor. Furthermore, compound 1 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that 1 could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1.</description><subject>Activin Receptors, Type II - antagonists & inhibitors</subject><subject>Activin Receptors, Type II - chemistry</subject><subject>Activin Receptors, Type II - metabolism</subject><subject>Amino Acid Sequence</subject><subject>Angiogenesis Inducing Agents - chemistry</subject><subject>Angiogenesis Inducing Agents - pharmacology</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Lactones - chemistry</subject><subject>Lactones - pharmacology</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Resorcinols - chemistry</subject><subject>Resorcinols - pharmacology</subject><subject>Sequence Alignment</subject><subject>Signal Transduction - drug effects</subject><subject>Smad Proteins - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtOwzAURS0EoqWwA4Q8ZECKP0nsDKuKQkUkJH7TyHGeVZd8ip1UYsYW2CIrIaUtQ0bPss-9Tz4InVMypoTRa6X9eFlBoRdQjeOc0FgkB2hII0aCUJLwEA0JYSxgMeMDdOL9khDCKePHaMAkJZywaIjcvIC6tcZq1dqmxo3B7QLwzDrf4icoQbd2DXiyGbbGj6Bh1TYuSO0b4HtbKw-Y4nm9sLnt76-w6pk1OG_zEvDr5rBtTb8_v4TkTIhTdGRU6eFsN0foZXbzPL0L0ofb-XSSBoqHsg20kiLOdQJKCG00ASESEwkoikhQk5swjnLGgchQcS0iBVzxxBSQF1wbkyR8hC63vSvXvHfg26yyXkNZqhqazmdUxjSSPJEbNNyi2jXeOzDZytlKuY-MkmxjO-ttZ3vb2c52H7vYbejy_u0vtNfbA2QL_MabztX9h__v_AEuxZBq</recordid><startdate>20170223</startdate><enddate>20170223</enddate><creator>Cho, Hanna</creator><creator>Sengupta, Sandip</creator><creator>Jeon, Sean S. H</creator><creator>Hur, Wooyoung</creator><creator>Choi, Hwan Geun</creator><creator>Seo, Hong-Seog</creator><creator>Lee, Byung Joo</creator><creator>Kim, Jeong Hun</creator><creator>Chung, Minhwan</creator><creator>Jeon, Noo Li</creator><creator>Kim, Nam Doo</creator><creator>Sim, Taebo</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><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3015-2059</orcidid></search><sort><creationdate>20170223</creationdate><title>Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L‑783277</title><author>Cho, Hanna ; Sengupta, Sandip ; Jeon, Sean S. H ; Hur, Wooyoung ; Choi, Hwan Geun ; Seo, Hong-Seog ; Lee, Byung Joo ; Kim, Jeong Hun ; Chung, Minhwan ; Jeon, Noo Li ; Kim, Nam Doo ; Sim, Taebo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-ca876bc9ea77cfc0e779f57edd571fbf465b23e084a3c75ae3a39fdebd3cff993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activin Receptors, Type II - antagonists & inhibitors</topic><topic>Activin Receptors, Type II - chemistry</topic><topic>Activin Receptors, Type II - metabolism</topic><topic>Amino Acid Sequence</topic><topic>Angiogenesis Inducing Agents - chemistry</topic><topic>Angiogenesis Inducing Agents - pharmacology</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Lactones - chemistry</topic><topic>Lactones - pharmacology</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Dynamics Simulation</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Resorcinols - chemistry</topic><topic>Resorcinols - pharmacology</topic><topic>Sequence Alignment</topic><topic>Signal Transduction - drug effects</topic><topic>Smad Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cho, Hanna</creatorcontrib><creatorcontrib>Sengupta, Sandip</creatorcontrib><creatorcontrib>Jeon, Sean S. 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H</au><au>Hur, Wooyoung</au><au>Choi, Hwan Geun</au><au>Seo, Hong-Seog</au><au>Lee, Byung Joo</au><au>Kim, Jeong Hun</au><au>Chung, Minhwan</au><au>Jeon, Noo Li</au><au>Kim, Nam Doo</au><au>Sim, Taebo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L‑783277</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-02-23</date><risdate>2017</risdate><volume>60</volume><issue>4</issue><spage>1495</spage><epage>1508</epage><pages>1495-1508</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1–6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4′ hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, 1 is the first selective ALK1 inhibitor. Furthermore, compound 1 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that 1 could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28103025</pmid><doi>10.1021/acs.jmedchem.6b01679</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-3015-2059</orcidid></addata></record> |
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| subjects | Activin Receptors, Type II - antagonists & inhibitors Activin Receptors, Type II - chemistry Activin Receptors, Type II - metabolism Amino Acid Sequence Angiogenesis Inducing Agents - chemistry Angiogenesis Inducing Agents - pharmacology Human Umbilical Vein Endothelial Cells Humans Lactones - chemistry Lactones - pharmacology Molecular Docking Simulation Molecular Dynamics Simulation Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Resorcinols - chemistry Resorcinols - pharmacology Sequence Alignment Signal Transduction - drug effects Smad Proteins - metabolism |
| title | Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L‑783277 |
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