Structure-Based Design of N‑(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S‑Transferase Omega 1 Inhibitors
Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystall...
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| Veröffentlicht in: | Journal of medicinal chemistry 2019-03, Vol.62 (6), p.3068-3087 |
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| container_title | Journal of medicinal chemistry |
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| creator | Dai, Weiyang Samanta, Soma Xue, Ding Petrunak, Elyse M Stuckey, Jeanne A Han, Yanyan Sun, Duxin Wu, Yong Neamati, Nouri |
| description | Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC50 = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy. |
| doi_str_mv | 10.1021/acs.jmedchem.8b01960 |
| format | Article |
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Advanced Photon Source (APS)</creatorcontrib><description>Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC50 = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.8b01960</identifier><identifier>PMID: 30735370</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acrylamides - chemistry ; Acrylamides - pharmacokinetics ; Acrylamides - pharmacology ; Amides ; Animals ; Anions ; Assays ; Catalytic Domain ; Chemical structure ; Crystallography, X-Ray ; Drug Design ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Glutathione Transferase - antagonists & inhibitors ; Half-Life ; HCT116 Cells ; Humans ; Inhibitors ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Mice ; Microsomes, Liver - enzymology ; Microsomes, Liver - metabolism ; Molecular Structure ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2019-03, Vol.62 (6), p.3068-3087</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a476t-ed2f6dc1415dc2d169296e4a8f7661751dca65f2c1ac43f8aa7d3fc006b4a7be3</citedby><cites>FETCH-LOGICAL-a476t-ed2f6dc1415dc2d169296e4a8f7661751dca65f2c1ac43f8aa7d3fc006b4a7be3</cites><orcidid>0000-0003-3291-7131 ; 0000-0003-0719-4963 ; 0000-0002-3222-4661 ; 0000000307194963 ; 0000000232224661 ; 0000000332917131</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.8b01960$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01960$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30735370$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1504972$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Dai, Weiyang</creatorcontrib><creatorcontrib>Samanta, Soma</creatorcontrib><creatorcontrib>Xue, Ding</creatorcontrib><creatorcontrib>Petrunak, Elyse M</creatorcontrib><creatorcontrib>Stuckey, Jeanne A</creatorcontrib><creatorcontrib>Han, Yanyan</creatorcontrib><creatorcontrib>Sun, Duxin</creatorcontrib><creatorcontrib>Wu, Yong</creatorcontrib><creatorcontrib>Neamati, Nouri</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Structure-Based Design of N‑(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S‑Transferase Omega 1 Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC50 = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy.</description><subject>Acrylamides - chemistry</subject><subject>Acrylamides - pharmacokinetics</subject><subject>Acrylamides - pharmacology</subject><subject>Amides</subject><subject>Animals</subject><subject>Anions</subject><subject>Assays</subject><subject>Catalytic Domain</subject><subject>Chemical structure</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glutathione Transferase - antagonists & inhibitors</subject><subject>Half-Life</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Mice</subject><subject>Microsomes, Liver - enzymology</subject><subject>Microsomes, Liver - metabolism</subject><subject>Molecular Structure</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAURi0EokPhDRCyWMEig38SJ7NBKgVKpaqt1LK27tg3E1eJXdlOpWGFeANekSfBZdoKNqy88Pede3UPIS85W3Im-DswaXk1oTUDTstuzfhKsUdkwRvBqrpj9WOyYEyISigh98izlK4YY5IL-ZTsSdbKRrZsQX5c5DibPEesPkBCSz9ichtPQ09Pf33_-aapzgf02zEPDr6FsRLVdnwLJm5HmJzFRCHR03CDIwVv6XnI6DM9GucMpRE80otCuYzgU4-xDKBnE26AcnrsB7d2OcT0nDzpYUz44u7dJ18_f7o8_FKdnB0dHx6cVFC3KldoRa-s4TVvrBGWq5VYKayh61uleNtwa0A1vTAcTC37DqC1sjeMqXUN7RrlPnm_417P69u7lU0jjPo6ugniVgdw-t8f7wa9CTe665pGqq4AXu8AIWWnk3EZzWCC92iy5g2rV60ooXoXMjGkFLF_GMCZvhWnizh9L07fiSu1V38v91C6N1UCbBf4Uw9z9OVW_2f-BriRrLo</recordid><startdate>20190328</startdate><enddate>20190328</enddate><creator>Dai, Weiyang</creator><creator>Samanta, Soma</creator><creator>Xue, Ding</creator><creator>Petrunak, Elyse M</creator><creator>Stuckey, Jeanne A</creator><creator>Han, Yanyan</creator><creator>Sun, Duxin</creator><creator>Wu, Yong</creator><creator>Neamati, Nouri</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</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>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3291-7131</orcidid><orcidid>https://orcid.org/0000-0003-0719-4963</orcidid><orcidid>https://orcid.org/0000-0002-3222-4661</orcidid><orcidid>https://orcid.org/0000000307194963</orcidid><orcidid>https://orcid.org/0000000232224661</orcidid><orcidid>https://orcid.org/0000000332917131</orcidid></search><sort><creationdate>20190328</creationdate><title>Structure-Based Design of N‑(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S‑Transferase Omega 1 Inhibitors</title><author>Dai, Weiyang ; Samanta, Soma ; Xue, Ding ; Petrunak, Elyse M ; Stuckey, Jeanne A ; Han, Yanyan ; Sun, Duxin ; Wu, Yong ; Neamati, Nouri</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a476t-ed2f6dc1415dc2d169296e4a8f7661751dca65f2c1ac43f8aa7d3fc006b4a7be3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acrylamides - chemistry</topic><topic>Acrylamides - pharmacokinetics</topic><topic>Acrylamides - pharmacology</topic><topic>Amides</topic><topic>Animals</topic><topic>Anions</topic><topic>Assays</topic><topic>Catalytic Domain</topic><topic>Chemical structure</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glutathione Transferase - antagonists & inhibitors</topic><topic>Half-Life</topic><topic>HCT116 Cells</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</topic><topic>Mice</topic><topic>Microsomes, Liver - enzymology</topic><topic>Microsomes, Liver - metabolism</topic><topic>Molecular Structure</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dai, Weiyang</creatorcontrib><creatorcontrib>Samanta, Soma</creatorcontrib><creatorcontrib>Xue, Ding</creatorcontrib><creatorcontrib>Petrunak, Elyse M</creatorcontrib><creatorcontrib>Stuckey, Jeanne A</creatorcontrib><creatorcontrib>Han, Yanyan</creatorcontrib><creatorcontrib>Sun, Duxin</creatorcontrib><creatorcontrib>Wu, Yong</creatorcontrib><creatorcontrib>Neamati, Nouri</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dai, Weiyang</au><au>Samanta, Soma</au><au>Xue, Ding</au><au>Petrunak, Elyse M</au><au>Stuckey, Jeanne A</au><au>Han, Yanyan</au><au>Sun, Duxin</au><au>Wu, Yong</au><au>Neamati, Nouri</au><aucorp>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Design of N‑(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S‑Transferase Omega 1 Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2019-03-28</date><risdate>2019</risdate><volume>62</volume><issue>6</issue><spage>3068</spage><epage>3087</epage><pages>3068-3087</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC50 = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>30735370</pmid><doi>10.1021/acs.jmedchem.8b01960</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-3291-7131</orcidid><orcidid>https://orcid.org/0000-0003-0719-4963</orcidid><orcidid>https://orcid.org/0000-0002-3222-4661</orcidid><orcidid>https://orcid.org/0000000307194963</orcidid><orcidid>https://orcid.org/0000000232224661</orcidid><orcidid>https://orcid.org/0000000332917131</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2019-03, Vol.62 (6), p.3068-3087 |
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| source | ACS Publications; MEDLINE |
| subjects | Acrylamides - chemistry Acrylamides - pharmacokinetics Acrylamides - pharmacology Amides Animals Anions Assays Catalytic Domain Chemical structure Crystallography, X-Ray Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Glutathione Transferase - antagonists & inhibitors Half-Life HCT116 Cells Humans Inhibitors INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Mice Microsomes, Liver - enzymology Microsomes, Liver - metabolism Molecular Structure Structure-Activity Relationship |
| title | Structure-Based Design of N‑(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S‑Transferase Omega 1 Inhibitors |
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