Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors
[Display omitted] •Discovery of novel chemotype of DNA topoisomerase II inhibitors.•Bacterial topoisomerase inhibitors were an excellent starting point in search of new topo II inhibitors.•The most potent inhibitor had an IC50 of 3.2 µM on topo II.•Two compounds showed very potent activity on MCF-7...
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| Veröffentlicht in: | Bioorganic chemistry 2020-09, Vol.102, p.104049-104049, Article 104049 |
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| container_title | Bioorganic chemistry |
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| creator | Skok, Žiga Durcik, Martina Gramec Skledar, Darja Barančoková, Michaela Peterlin Mašič, Lucija Tomašič, Tihomir Zega, Anamarija Kikelj, Danijel Zidar, Nace Ilaš, Janez |
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•Discovery of novel chemotype of DNA topoisomerase II inhibitors.•Bacterial topoisomerase inhibitors were an excellent starting point in search of new topo II inhibitors.•The most potent inhibitor had an IC50 of 3.2 µM on topo II.•Two compounds showed very potent activity on MCF-7 cell line (IC50 |
| doi_str_mv | 10.1016/j.bioorg.2020.104049 |
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•Discovery of novel chemotype of DNA topoisomerase II inhibitors.•Bacterial topoisomerase inhibitors were an excellent starting point in search of new topo II inhibitors.•The most potent inhibitor had an IC50 of 3.2 µM on topo II.•Two compounds showed very potent activity on MCF-7 cell line (IC50 < 10 µM).
Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 µM) and ATPase assay (IC50 = 0.43 µM). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 µM, respectively.</description><identifier>ISSN: 0045-2068</identifier><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2020.104049</identifier><identifier>PMID: 32688116</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine Triphosphatases - metabolism ; Anticancer drug ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; ATP-competitive inhibitor ; Biological screening ; DNA topoisomerase II ; DNA Topoisomerases, Type II - chemistry ; Humans ; Molecular Docking Simulation ; N-phenylpyrrolamide ; Topoisomerase II Inhibitors - pharmacology ; Topoisomerase II Inhibitors - therapeutic use</subject><ispartof>Bioorganic chemistry, 2020-09, Vol.102, p.104049-104049, Article 104049</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-dc5b3dfb2071dc734bed0316cada375f9a4e430a95aaef60af43122333435023</citedby><cites>FETCH-LOGICAL-c362t-dc5b3dfb2071dc734bed0316cada375f9a4e430a95aaef60af43122333435023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0045206820313468$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32688116$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Skok, Žiga</creatorcontrib><creatorcontrib>Durcik, Martina</creatorcontrib><creatorcontrib>Gramec Skledar, Darja</creatorcontrib><creatorcontrib>Barančoková, Michaela</creatorcontrib><creatorcontrib>Peterlin Mašič, Lucija</creatorcontrib><creatorcontrib>Tomašič, Tihomir</creatorcontrib><creatorcontrib>Zega, Anamarija</creatorcontrib><creatorcontrib>Kikelj, Danijel</creatorcontrib><creatorcontrib>Zidar, Nace</creatorcontrib><creatorcontrib>Ilaš, Janez</creatorcontrib><title>Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors</title><title>Bioorganic chemistry</title><addtitle>Bioorg Chem</addtitle><description>[Display omitted]
•Discovery of novel chemotype of DNA topoisomerase II inhibitors.•Bacterial topoisomerase inhibitors were an excellent starting point in search of new topo II inhibitors.•The most potent inhibitor had an IC50 of 3.2 µM on topo II.•Two compounds showed very potent activity on MCF-7 cell line (IC50 < 10 µM).
Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 µM) and ATPase assay (IC50 = 0.43 µM). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 µM, respectively.</description><subject>Adenosine Triphosphatases - metabolism</subject><subject>Anticancer drug</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>ATP-competitive inhibitor</subject><subject>Biological screening</subject><subject>DNA topoisomerase II</subject><subject>DNA Topoisomerases, Type II - chemistry</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>N-phenylpyrrolamide</subject><subject>Topoisomerase II Inhibitors - pharmacology</subject><subject>Topoisomerase II Inhibitors - therapeutic use</subject><issn>0045-2068</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtu2zAQRYmiQeMm_YOi4LIbOcOHXpsCRtykBoIkC-8JihrZNCzRJSkHWeeL-iP5pkhQ0gJdZDXA4Nw7mEPIVwZzBiy72M0r65zfzDnwcSVBlh_IjEEJCWccPpIZgEwTDllxSj6HsANgTObZJ3IqeFYUjGUz8rS0wbgj-kfqGtrhA12s7xPj2gNGG-0Rqe22trLR-TAS277VHV3eLmh0B2eDa9HrgHS1ev5D49a7frOlwXjEznabMVFpE9Fbvf8v8a_3nJw0eh_wy-s8I-urn-vLX8nN3fXqcnGTGJHxmNQmrUTdVBxyVptcyAprECwzutYiT5tSS5QCdJlqjU0GupGCcS6EkCIFLs7I96n24N3vHkNU7fA77ve6Q9cHxSVPizLP82JA5YQa70Lw2KiDt632j4qBGu2rnZrsq9G-muwPsW-vF_qqxfpv6E33APyYABzePFr0KhiLncHaejRR1c6-f-EFl0Ca8w</recordid><startdate>202009</startdate><enddate>202009</enddate><creator>Skok, Žiga</creator><creator>Durcik, Martina</creator><creator>Gramec Skledar, Darja</creator><creator>Barančoková, Michaela</creator><creator>Peterlin Mašič, Lucija</creator><creator>Tomašič, Tihomir</creator><creator>Zega, Anamarija</creator><creator>Kikelj, Danijel</creator><creator>Zidar, Nace</creator><creator>Ilaš, Janez</creator><general>Elsevier 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>7X8</scope></search><sort><creationdate>202009</creationdate><title>Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors</title><author>Skok, Žiga ; Durcik, Martina ; Gramec Skledar, Darja ; Barančoková, Michaela ; Peterlin Mašič, Lucija ; Tomašič, Tihomir ; Zega, Anamarija ; Kikelj, Danijel ; Zidar, Nace ; Ilaš, Janez</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-dc5b3dfb2071dc734bed0316cada375f9a4e430a95aaef60af43122333435023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenosine Triphosphatases - metabolism</topic><topic>Anticancer drug</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>ATP-competitive inhibitor</topic><topic>Biological screening</topic><topic>DNA topoisomerase II</topic><topic>DNA Topoisomerases, Type II - chemistry</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>N-phenylpyrrolamide</topic><topic>Topoisomerase II Inhibitors - pharmacology</topic><topic>Topoisomerase II Inhibitors - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Skok, Žiga</creatorcontrib><creatorcontrib>Durcik, Martina</creatorcontrib><creatorcontrib>Gramec Skledar, Darja</creatorcontrib><creatorcontrib>Barančoková, Michaela</creatorcontrib><creatorcontrib>Peterlin Mašič, Lucija</creatorcontrib><creatorcontrib>Tomašič, Tihomir</creatorcontrib><creatorcontrib>Zega, Anamarija</creatorcontrib><creatorcontrib>Kikelj, Danijel</creatorcontrib><creatorcontrib>Zidar, Nace</creatorcontrib><creatorcontrib>Ilaš, Janez</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>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Skok, Žiga</au><au>Durcik, Martina</au><au>Gramec Skledar, Darja</au><au>Barančoková, Michaela</au><au>Peterlin Mašič, Lucija</au><au>Tomašič, Tihomir</au><au>Zega, Anamarija</au><au>Kikelj, Danijel</au><au>Zidar, Nace</au><au>Ilaš, Janez</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2020-09</date><risdate>2020</risdate><volume>102</volume><spage>104049</spage><epage>104049</epage><pages>104049-104049</pages><artnum>104049</artnum><issn>0045-2068</issn><eissn>1090-2120</eissn><abstract>[Display omitted]
•Discovery of novel chemotype of DNA topoisomerase II inhibitors.•Bacterial topoisomerase inhibitors were an excellent starting point in search of new topo II inhibitors.•The most potent inhibitor had an IC50 of 3.2 µM on topo II.•Two compounds showed very potent activity on MCF-7 cell line (IC50 < 10 µM).
Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC50 = 3.2 µM) and ATPase assay (IC50 = 0.43 µM). Cytotoxic activity of all hits was determined in MCF-7 cancer cell line and the most potent compounds, 16 and 20, showed an IC50 value of 8.7 and 8.2 µM, respectively.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32688116</pmid><doi>10.1016/j.bioorg.2020.104049</doi><tpages>1</tpages></addata></record> |
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| subjects | Adenosine Triphosphatases - metabolism Anticancer drug Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use ATP-competitive inhibitor Biological screening DNA topoisomerase II DNA Topoisomerases, Type II - chemistry Humans Molecular Docking Simulation N-phenylpyrrolamide Topoisomerase II Inhibitors - pharmacology Topoisomerase II Inhibitors - therapeutic use |
| title | Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors |
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