A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition
Glycogen synthase kinase 3β (GSK‐3β) and casein kinase 1δ (CK‐1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking‐based design. Compound 12, 3‐(7‐amino‐5‐(cyclohexylamino...
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| Veröffentlicht in: | ChemMedChem 2019-02, Vol.14 (3), p.310-314 |
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| creator | Redenti, Sara Marcovich, Irene De Vita, Teresa Pérez, Concepción De Zorzi, Rita Demitri, Nicola Perez, Daniel I. Bottegoni, Giovanni Bisignano, Paola Bissaro, Maicol Moro, Stefano Martinez, Ana Storici, Paola Spalluto, Giampiero Cavalli, Andrea Federico, Stephanie |
| description | Glycogen synthase kinase 3β (GSK‐3β) and casein kinase 1δ (CK‐1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking‐based design. Compound 12, 3‐(7‐amino‐5‐(cyclohexylamino)‐[1,2,4]triazolo[1,5‐a][1,3,5]triazin‐2‐yl)‐2‐cyanoacrylamide, showed combined inhibitory activity against GSK‐3β and CK‐1δ [IC50(GSK‐3β)=0.17 μm; IC50(CK‐1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK‐1δ, and a co‐crystal of compound 12 inside GSK‐3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK‐3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK‐3β/CK‐1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.
Good polypharmacology: A dual inhibitor of GSK‐3β and CK‐1δ kinases was discovered. Compound 12 is an ATP‐competitive inhibitor of CK‐1δ and a covalent inhibitor of GSK‐3β. It showed neuroprotective activity in preliminary in vitro tests, suggesting further investigations to validate this dual inhibition as a promising strategy for treating neuroinflammatory disorders such as Parkinson's disease. |
| doi_str_mv | 10.1002/cmdc.201800778 |
| format | Article |
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Good polypharmacology: A dual inhibitor of GSK‐3β and CK‐1δ kinases was discovered. Compound 12 is an ATP‐competitive inhibitor of CK‐1δ and a covalent inhibitor of GSK‐3β. It showed neuroprotective activity in preliminary in vitro tests, suggesting further investigations to validate this dual inhibition as a promising strategy for treating neuroinflammatory disorders such as Parkinson's disease.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201800778</identifier><identifier>PMID: 30548443</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Animals ; Casein ; Casein Kinase Idelta - antagonists & inhibitors ; Casein Kinase Idelta - metabolism ; casein kinase 1δ ; Cell Survival ; Crystallography, X-Ray ; Cytotoxicity ; Docking ; Dose-Response Relationship, Drug ; Glycogen ; Glycogen synthase kinase 3 ; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors ; Glycogen Synthase Kinase 3 beta - metabolism ; glycogen synthase kinase 3β ; Humans ; Inflammation ; Inhibition ; Kinases ; Ligands ; Medical treatment ; Models, Molecular ; Molecular Structure ; Movement disorders ; Neurodegenerative diseases ; neuroinflammation ; Neuroprotection ; Neuroprotective Agents - chemical synthesis ; Neuroprotective Agents - chemistry ; Neuroprotective Agents - pharmacology ; Parkinson's disease ; PC12 Cells ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Rats ; Structure-Activity Relationship ; thia-Michael reaction ; Triazines - chemical synthesis ; Triazines - chemistry ; Triazines - pharmacology</subject><ispartof>ChemMedChem, 2019-02, Vol.14 (3), p.310-314</ispartof><rights>2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4138-bd560a4a39e33c9f7a5a0193e86cccbbea7692487064a9c268fa980da4f807b03</citedby><cites>FETCH-LOGICAL-c4138-bd560a4a39e33c9f7a5a0193e86cccbbea7692487064a9c268fa980da4f807b03</cites><orcidid>0000-0003-2800-5287</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201800778$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201800778$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30548443$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Redenti, Sara</creatorcontrib><creatorcontrib>Marcovich, Irene</creatorcontrib><creatorcontrib>De Vita, Teresa</creatorcontrib><creatorcontrib>Pérez, Concepción</creatorcontrib><creatorcontrib>De Zorzi, Rita</creatorcontrib><creatorcontrib>Demitri, Nicola</creatorcontrib><creatorcontrib>Perez, Daniel I.</creatorcontrib><creatorcontrib>Bottegoni, Giovanni</creatorcontrib><creatorcontrib>Bisignano, Paola</creatorcontrib><creatorcontrib>Bissaro, Maicol</creatorcontrib><creatorcontrib>Moro, Stefano</creatorcontrib><creatorcontrib>Martinez, Ana</creatorcontrib><creatorcontrib>Storici, Paola</creatorcontrib><creatorcontrib>Spalluto, Giampiero</creatorcontrib><creatorcontrib>Cavalli, Andrea</creatorcontrib><creatorcontrib>Federico, Stephanie</creatorcontrib><title>A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>Glycogen synthase kinase 3β (GSK‐3β) and casein kinase 1δ (CK‐1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking‐based design. Compound 12, 3‐(7‐amino‐5‐(cyclohexylamino)‐[1,2,4]triazolo[1,5‐a][1,3,5]triazin‐2‐yl)‐2‐cyanoacrylamide, showed combined inhibitory activity against GSK‐3β and CK‐1δ [IC50(GSK‐3β)=0.17 μm; IC50(CK‐1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK‐1δ, and a co‐crystal of compound 12 inside GSK‐3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK‐3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK‐3β/CK‐1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.
Good polypharmacology: A dual inhibitor of GSK‐3β and CK‐1δ kinases was discovered. Compound 12 is an ATP‐competitive inhibitor of CK‐1δ and a covalent inhibitor of GSK‐3β. It showed neuroprotective activity in preliminary in vitro tests, suggesting further investigations to validate this dual inhibition as a promising strategy for treating neuroinflammatory disorders such as Parkinson's disease.</description><subject>Animals</subject><subject>Casein</subject><subject>Casein Kinase Idelta - antagonists & inhibitors</subject><subject>Casein Kinase Idelta - metabolism</subject><subject>casein kinase 1δ</subject><subject>Cell Survival</subject><subject>Crystallography, X-Ray</subject><subject>Cytotoxicity</subject><subject>Docking</subject><subject>Dose-Response Relationship, Drug</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogen Synthase Kinase 3 beta - antagonists & inhibitors</subject><subject>Glycogen Synthase Kinase 3 beta - metabolism</subject><subject>glycogen synthase kinase 3β</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inhibition</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Medical treatment</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>neuroinflammation</subject><subject>Neuroprotection</subject><subject>Neuroprotective Agents - chemical synthesis</subject><subject>Neuroprotective Agents - chemistry</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Parkinson's disease</subject><subject>PC12 Cells</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>thia-Michael reaction</subject><subject>Triazines - chemical synthesis</subject><subject>Triazines - chemistry</subject><subject>Triazines - pharmacology</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQxi0EoqVw5YgsceGyWzt2Yvu4ZEup2EIllnM0cZytq8QudkK1PfEInHkMxHP0IXgSHG1ZJC6c5t9vPo3mQ-g5JXNKSHas-0bPM0IlIULIB-iQyoLMBJXi4T4X6gA9ifGKEM4llY_RASM5l5yzQ_R9gdfBwq3v_DBF68yvr99eQzQNXo7Q4dOP71KD3f04LqeE3v3EK7sB12CIGPCFH4wbbALfmzH465BqPdgvBi82aYAvgokT4DZ4fePx0ratCdPg3OhLcDb2EfsWn7jbbQ-D1fjMXdraDta7p-hRC100z-7jEfr05mRdvp2tPpyelYvVTHPK5Kxu8oIAB6YMY1q1AnIgVDEjC611XRsQhcq4FKTgoHRWyBaUJA3wVhJRE3aEXu100_GfRxOHqrdRm64DZ_wYq4zmoigYJTyhL_9Br_wYXLouUSJXjKcPJ2q-o3TwMQbTVtfB9hC2FSXV5Fo1uVbtXUsLL-5lx7o3zR7_Y1MC1A64sZ3Z_keuKs-X5V_x3-ZzqOc</recordid><startdate>20190205</startdate><enddate>20190205</enddate><creator>Redenti, Sara</creator><creator>Marcovich, Irene</creator><creator>De Vita, Teresa</creator><creator>Pérez, Concepción</creator><creator>De Zorzi, Rita</creator><creator>Demitri, Nicola</creator><creator>Perez, Daniel I.</creator><creator>Bottegoni, Giovanni</creator><creator>Bisignano, Paola</creator><creator>Bissaro, Maicol</creator><creator>Moro, Stefano</creator><creator>Martinez, Ana</creator><creator>Storici, Paola</creator><creator>Spalluto, Giampiero</creator><creator>Cavalli, Andrea</creator><creator>Federico, Stephanie</creator><general>Wiley Subscription Services, Inc</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>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2800-5287</orcidid></search><sort><creationdate>20190205</creationdate><title>A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition</title><author>Redenti, Sara ; Marcovich, Irene ; De Vita, Teresa ; Pérez, Concepción ; De Zorzi, Rita ; Demitri, Nicola ; Perez, Daniel I. ; Bottegoni, Giovanni ; Bisignano, Paola ; Bissaro, Maicol ; Moro, Stefano ; Martinez, Ana ; Storici, Paola ; Spalluto, Giampiero ; Cavalli, Andrea ; Federico, Stephanie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4138-bd560a4a39e33c9f7a5a0193e86cccbbea7692487064a9c268fa980da4f807b03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Casein</topic><topic>Casein Kinase Idelta - antagonists & inhibitors</topic><topic>Casein Kinase Idelta - metabolism</topic><topic>casein kinase 1δ</topic><topic>Cell Survival</topic><topic>Crystallography, X-Ray</topic><topic>Cytotoxicity</topic><topic>Docking</topic><topic>Dose-Response Relationship, Drug</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogen Synthase Kinase 3 beta - antagonists & inhibitors</topic><topic>Glycogen Synthase Kinase 3 beta - metabolism</topic><topic>glycogen synthase kinase 3β</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Inhibition</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Medical treatment</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>neuroinflammation</topic><topic>Neuroprotection</topic><topic>Neuroprotective Agents - chemical synthesis</topic><topic>Neuroprotective Agents - chemistry</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Parkinson's disease</topic><topic>PC12 Cells</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>thia-Michael reaction</topic><topic>Triazines - chemical synthesis</topic><topic>Triazines - chemistry</topic><topic>Triazines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Redenti, Sara</creatorcontrib><creatorcontrib>Marcovich, Irene</creatorcontrib><creatorcontrib>De Vita, Teresa</creatorcontrib><creatorcontrib>Pérez, Concepción</creatorcontrib><creatorcontrib>De Zorzi, Rita</creatorcontrib><creatorcontrib>Demitri, Nicola</creatorcontrib><creatorcontrib>Perez, Daniel I.</creatorcontrib><creatorcontrib>Bottegoni, Giovanni</creatorcontrib><creatorcontrib>Bisignano, Paola</creatorcontrib><creatorcontrib>Bissaro, Maicol</creatorcontrib><creatorcontrib>Moro, Stefano</creatorcontrib><creatorcontrib>Martinez, Ana</creatorcontrib><creatorcontrib>Storici, Paola</creatorcontrib><creatorcontrib>Spalluto, Giampiero</creatorcontrib><creatorcontrib>Cavalli, Andrea</creatorcontrib><creatorcontrib>Federico, Stephanie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Redenti, Sara</au><au>Marcovich, Irene</au><au>De Vita, Teresa</au><au>Pérez, Concepción</au><au>De Zorzi, Rita</au><au>Demitri, Nicola</au><au>Perez, Daniel I.</au><au>Bottegoni, Giovanni</au><au>Bisignano, Paola</au><au>Bissaro, Maicol</au><au>Moro, Stefano</au><au>Martinez, Ana</au><au>Storici, Paola</au><au>Spalluto, Giampiero</au><au>Cavalli, Andrea</au><au>Federico, Stephanie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2019-02-05</date><risdate>2019</risdate><volume>14</volume><issue>3</issue><spage>310</spage><epage>314</epage><pages>310-314</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>Glycogen synthase kinase 3β (GSK‐3β) and casein kinase 1δ (CK‐1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking‐based design. Compound 12, 3‐(7‐amino‐5‐(cyclohexylamino)‐[1,2,4]triazolo[1,5‐a][1,3,5]triazin‐2‐yl)‐2‐cyanoacrylamide, showed combined inhibitory activity against GSK‐3β and CK‐1δ [IC50(GSK‐3β)=0.17 μm; IC50(CK‐1δ)=0.68 μm]. In particular, classical ATP competition was observed against CK‐1δ, and a co‐crystal of compound 12 inside GSK‐3β confirmed a covalent interaction between the cyanoacrylamide warhead and Cys199, which could help in the development of more potent covalent inhibitors of GSK‐3β. Preliminary studies on in vitro models of Parkinson's disease revealed that compound 12 is not cytotoxic and shows neuroprotective activity. These results encourage further investigations to validate GSK‐3β/CK‐1δ inhibition as a possible new strategy to treat neuroinflammatory/degenerative diseases.
Good polypharmacology: A dual inhibitor of GSK‐3β and CK‐1δ kinases was discovered. Compound 12 is an ATP‐competitive inhibitor of CK‐1δ and a covalent inhibitor of GSK‐3β. It showed neuroprotective activity in preliminary in vitro tests, suggesting further investigations to validate this dual inhibition as a promising strategy for treating neuroinflammatory disorders such as Parkinson's disease.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30548443</pmid><doi>10.1002/cmdc.201800778</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0003-2800-5287</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Casein Casein Kinase Idelta - antagonists & inhibitors Casein Kinase Idelta - metabolism casein kinase 1δ Cell Survival Crystallography, X-Ray Cytotoxicity Docking Dose-Response Relationship, Drug Glycogen Glycogen synthase kinase 3 Glycogen Synthase Kinase 3 beta - antagonists & inhibitors Glycogen Synthase Kinase 3 beta - metabolism glycogen synthase kinase 3β Humans Inflammation Inhibition Kinases Ligands Medical treatment Models, Molecular Molecular Structure Movement disorders Neurodegenerative diseases neuroinflammation Neuroprotection Neuroprotective Agents - chemical synthesis Neuroprotective Agents - chemistry Neuroprotective Agents - pharmacology Parkinson's disease PC12 Cells Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Rats Structure-Activity Relationship thia-Michael reaction Triazines - chemical synthesis Triazines - chemistry Triazines - pharmacology |
| title | A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition |
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