In Silico Discovery of 5′-Modified 7‑Deoxy-7-ethynyl-4′-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor
Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional phar...
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creator | Kwon, Eun-Ji Mashelkar, Karishma K. Seo, Juhee Shin, Yoon-Ze Sung, Kisu Jang, Sung Chul Cheon, Sang Won Lee, Haeseung Lee, Hyuk Woo Kim, Gyudong Han, Byung Woo Lee, Sang Kook Jeong, Lak Shin Cha, Hyuk-Jin |
description | Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional pharmacophores poses a technical challenge as this atypical kinase shares slight similarities with eukaryotic protein kinases. Chemically modifying a cytotoxic 4′-thioadenosine analogue through high genotoxicity yielded several novel nongenotoxic kinase inhibitors. In silico apporoaches utilizing transcriptomic and chemical similarities with known compounds and KINOMEscan profiles unveiled the HASPIN inhibitor LJ4827. LJ4827’s specificity and potency as a HASPIN inhibitor were verified through in vitro kinase assay and X-ray crystallography. HASPIN inhibition by LJ4827 reduced histone H3 phosphorylation and impeded Aurora B recruitment in cancer cell centromeres but not in noncancer cells. Through transcriptome analysis of lung cancer patients, PLK1 was determined as a druggable synergistic partner to complement HASPIN inhibition. Chemical or genetic PLK1 perturbation with LJ4827 effectuated pronounced lung cancer cytotoxicity in vitro and in vivo. Therefore, LJ4827 is a novel anticancer therapeutic for selectively impeding cancer mitosis through potent HASPIN inhibition, and simultaneous HASPIN and PLK1 interference is a promising therapeutic strategy for lung cancer. |
doi_str_mv | 10.1021/acscentsci.3c00332 |
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However, developing a HASPIN inhibitor from conventional pharmacophores poses a technical challenge as this atypical kinase shares slight similarities with eukaryotic protein kinases. Chemically modifying a cytotoxic 4′-thioadenosine analogue through high genotoxicity yielded several novel nongenotoxic kinase inhibitors. In silico apporoaches utilizing transcriptomic and chemical similarities with known compounds and KINOMEscan profiles unveiled the HASPIN inhibitor LJ4827. LJ4827’s specificity and potency as a HASPIN inhibitor were verified through in vitro kinase assay and X-ray crystallography. HASPIN inhibition by LJ4827 reduced histone H3 phosphorylation and impeded Aurora B recruitment in cancer cell centromeres but not in noncancer cells. Through transcriptome analysis of lung cancer patients, PLK1 was determined as a druggable synergistic partner to complement HASPIN inhibition. Chemical or genetic PLK1 perturbation with LJ4827 effectuated pronounced lung cancer cytotoxicity in vitro and in vivo. Therefore, LJ4827 is a novel anticancer therapeutic for selectively impeding cancer mitosis through potent HASPIN inhibition, and simultaneous HASPIN and PLK1 interference is a promising therapeutic strategy for lung cancer.</description><identifier>ISSN: 2374-7943</identifier><identifier>EISSN: 2374-7951</identifier><identifier>DOI: 10.1021/acscentsci.3c00332</identifier><identifier>PMID: 37396870</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animal models ; Anticancer properties ; Aurora B protein ; Biocompatibility ; Cancer ; Cell cycle ; Centromeres ; Chemical fingerprinting ; Crystallography ; Cytotoxicity ; Genotoxicity ; Histone H3 ; Histones ; Hydrogen bonds ; Kinases ; Lethality ; Lung cancer ; Mitosis ; Perturbation ; Pharmacophores ; Phosphorylation ; Polo-like kinase 1 ; Similarity ; Stem cells ; Transcriptomes ; Transcriptomics ; X-ray crystallography ; Yeast</subject><ispartof>ACS central science, 2023-06, Vol.9 (6), p.1140-1149</ispartof><rights>2023 The Authors. Published by American Chemical Society</rights><rights>2023 The Authors. Published by American Chemical Society.</rights><rights>2023. This work is licensed under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 The Authors. Published by American Chemical Society 2023 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a470t-8dd0deafdf1d3ec6b28e6fa238ca28119eb8b7692bb5df6a0d99a72467916723</citedby><cites>FETCH-LOGICAL-a470t-8dd0deafdf1d3ec6b28e6fa238ca28119eb8b7692bb5df6a0d99a72467916723</cites><orcidid>0000-0001-9277-2662 ; 0000-0002-4306-7024 ; 0000-0002-3441-707X</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/acscentsci.3c00332$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2913138817?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,21388,21389,21390,21391,23256,27080,27924,27925,33530,33531,33703,33704,33744,33745,34005,34006,34314,34315,43659,43787,43805,43953,44067,53791,53793,56762,56812,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37396870$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kwon, Eun-Ji</creatorcontrib><creatorcontrib>Mashelkar, Karishma K.</creatorcontrib><creatorcontrib>Seo, Juhee</creatorcontrib><creatorcontrib>Shin, Yoon-Ze</creatorcontrib><creatorcontrib>Sung, Kisu</creatorcontrib><creatorcontrib>Jang, Sung Chul</creatorcontrib><creatorcontrib>Cheon, Sang Won</creatorcontrib><creatorcontrib>Lee, Haeseung</creatorcontrib><creatorcontrib>Lee, Hyuk Woo</creatorcontrib><creatorcontrib>Kim, Gyudong</creatorcontrib><creatorcontrib>Han, Byung Woo</creatorcontrib><creatorcontrib>Lee, Sang Kook</creatorcontrib><creatorcontrib>Jeong, Lak Shin</creatorcontrib><creatorcontrib>Cha, Hyuk-Jin</creatorcontrib><title>In Silico Discovery of 5′-Modified 7‑Deoxy-7-ethynyl-4′-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor</title><title>ACS central science</title><addtitle>ACS Cent. 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Therefore, LJ4827 is a novel anticancer therapeutic for selectively impeding cancer mitosis through potent HASPIN inhibition, and simultaneous HASPIN and PLK1 interference is a promising therapeutic strategy for lung cancer.</description><subject>Animal models</subject><subject>Anticancer properties</subject><subject>Aurora B protein</subject><subject>Biocompatibility</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Centromeres</subject><subject>Chemical fingerprinting</subject><subject>Crystallography</subject><subject>Cytotoxicity</subject><subject>Genotoxicity</subject><subject>Histone H3</subject><subject>Histones</subject><subject>Hydrogen bonds</subject><subject>Kinases</subject><subject>Lethality</subject><subject>Lung cancer</subject><subject>Mitosis</subject><subject>Perturbation</subject><subject>Pharmacophores</subject><subject>Phosphorylation</subject><subject>Polo-like kinase 1</subject><subject>Similarity</subject><subject>Stem cells</subject><subject>Transcriptomes</subject><subject>Transcriptomics</subject><subject>X-ray crystallography</subject><subject>Yeast</subject><issn>2374-7943</issn><issn>2374-7951</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kk9u1DAUxiMEolXpBVggS2zYZPCfjJ2s0KgtbcQAlaZ7y7FfGlcZu9ielux6hZ6AO3CknoSMZpgBFkiWbcm_77Pf85dlrwmeEEzJe6WjBpeithOmMWaMPssOKRNFLqopeb7bF-wgO47xBmNMCs6nVLzMDphgFS8FPsx-1A4tbG-1R6c2an8HYUC-RdOnh5_5Z29sa8Eg8fTweAr--5CLHFI3uKHPizWROuuVAeejdYBURApdzBaX9RdUu842NvmAlDOoThEtBgfh2sZkNZq5cVZOQ0BnbQs6oXubOpQ6QJfzT2SvfpW9aFUf4Xi7HmVXH8-uTi7y-dfz-mQ2z1UhcMpLY7AB1ZqWGAaaN7QE3irKSq1oSUgFTdkIXtGmmZqWK2yqSglacFERLig7yj5sbG9XzRLMurNB9fI22KUKg_TKyr9PnO3ktb-TBDNCOCejw7utQ_DfVhCTXI79hL5XDvwqSlqycVSsxCP69h_0xq-CG8uTtCKMsLIkYqTohtLBxxig3b2GYLmOgNxHQG4jMIre_FnHTvL7w0dgsgFG8f7a_zj-At0qw0Q</recordid><startdate>20230628</startdate><enddate>20230628</enddate><creator>Kwon, Eun-Ji</creator><creator>Mashelkar, Karishma K.</creator><creator>Seo, Juhee</creator><creator>Shin, Yoon-Ze</creator><creator>Sung, Kisu</creator><creator>Jang, Sung Chul</creator><creator>Cheon, Sang Won</creator><creator>Lee, Haeseung</creator><creator>Lee, Hyuk Woo</creator><creator>Kim, Gyudong</creator><creator>Han, Byung Woo</creator><creator>Lee, Sang Kook</creator><creator>Jeong, Lak Shin</creator><creator>Cha, Hyuk-Jin</creator><general>American Chemical Society</general><scope>N~.</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7XB</scope><scope>88I</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>KB.</scope><scope>L6V</scope><scope>LK8</scope><scope>M2P</scope><scope>M7P</scope><scope>M7S</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9277-2662</orcidid><orcidid>https://orcid.org/0000-0002-4306-7024</orcidid><orcidid>https://orcid.org/0000-0002-3441-707X</orcidid></search><sort><creationdate>20230628</creationdate><title>In Silico Discovery of 5′-Modified 7‑Deoxy-7-ethynyl-4′-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor</title><author>Kwon, Eun-Ji ; Mashelkar, Karishma K. ; Seo, Juhee ; Shin, Yoon-Ze ; Sung, Kisu ; Jang, Sung Chul ; Cheon, Sang Won ; Lee, Haeseung ; Lee, Hyuk Woo ; Kim, Gyudong ; Han, Byung Woo ; Lee, Sang Kook ; Jeong, Lak Shin ; Cha, Hyuk-Jin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a470t-8dd0deafdf1d3ec6b28e6fa238ca28119eb8b7692bb5df6a0d99a72467916723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animal models</topic><topic>Anticancer properties</topic><topic>Aurora B protein</topic><topic>Biocompatibility</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Centromeres</topic><topic>Chemical fingerprinting</topic><topic>Crystallography</topic><topic>Cytotoxicity</topic><topic>Genotoxicity</topic><topic>Histone H3</topic><topic>Histones</topic><topic>Hydrogen bonds</topic><topic>Kinases</topic><topic>Lethality</topic><topic>Lung cancer</topic><topic>Mitosis</topic><topic>Perturbation</topic><topic>Pharmacophores</topic><topic>Phosphorylation</topic><topic>Polo-like kinase 1</topic><topic>Similarity</topic><topic>Stem cells</topic><topic>Transcriptomes</topic><topic>Transcriptomics</topic><topic>X-ray crystallography</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kwon, Eun-Ji</creatorcontrib><creatorcontrib>Mashelkar, Karishma K.</creatorcontrib><creatorcontrib>Seo, Juhee</creatorcontrib><creatorcontrib>Shin, Yoon-Ze</creatorcontrib><creatorcontrib>Sung, Kisu</creatorcontrib><creatorcontrib>Jang, Sung Chul</creatorcontrib><creatorcontrib>Cheon, Sang Won</creatorcontrib><creatorcontrib>Lee, Haeseung</creatorcontrib><creatorcontrib>Lee, Hyuk Woo</creatorcontrib><creatorcontrib>Kim, Gyudong</creatorcontrib><creatorcontrib>Han, Byung Woo</creatorcontrib><creatorcontrib>Lee, Sang Kook</creatorcontrib><creatorcontrib>Jeong, Lak Shin</creatorcontrib><creatorcontrib>Cha, Hyuk-Jin</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>Materials Science Database</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS central science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kwon, Eun-Ji</au><au>Mashelkar, Karishma K.</au><au>Seo, Juhee</au><au>Shin, Yoon-Ze</au><au>Sung, Kisu</au><au>Jang, Sung Chul</au><au>Cheon, Sang Won</au><au>Lee, Haeseung</au><au>Lee, Hyuk Woo</au><au>Kim, Gyudong</au><au>Han, Byung Woo</au><au>Lee, Sang Kook</au><au>Jeong, Lak Shin</au><au>Cha, Hyuk-Jin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Silico Discovery of 5′-Modified 7‑Deoxy-7-ethynyl-4′-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor</atitle><jtitle>ACS central science</jtitle><addtitle>ACS Cent. Sci</addtitle><date>2023-06-28</date><risdate>2023</risdate><volume>9</volume><issue>6</issue><spage>1140</spage><epage>1149</epage><pages>1140-1149</pages><issn>2374-7943</issn><eissn>2374-7951</eissn><abstract>Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional pharmacophores poses a technical challenge as this atypical kinase shares slight similarities with eukaryotic protein kinases. Chemically modifying a cytotoxic 4′-thioadenosine analogue through high genotoxicity yielded several novel nongenotoxic kinase inhibitors. In silico apporoaches utilizing transcriptomic and chemical similarities with known compounds and KINOMEscan profiles unveiled the HASPIN inhibitor LJ4827. LJ4827’s specificity and potency as a HASPIN inhibitor were verified through in vitro kinase assay and X-ray crystallography. HASPIN inhibition by LJ4827 reduced histone H3 phosphorylation and impeded Aurora B recruitment in cancer cell centromeres but not in noncancer cells. Through transcriptome analysis of lung cancer patients, PLK1 was determined as a druggable synergistic partner to complement HASPIN inhibition. Chemical or genetic PLK1 perturbation with LJ4827 effectuated pronounced lung cancer cytotoxicity in vitro and in vivo. 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subjects | Animal models Anticancer properties Aurora B protein Biocompatibility Cancer Cell cycle Centromeres Chemical fingerprinting Crystallography Cytotoxicity Genotoxicity Histone H3 Histones Hydrogen bonds Kinases Lethality Lung cancer Mitosis Perturbation Pharmacophores Phosphorylation Polo-like kinase 1 Similarity Stem cells Transcriptomes Transcriptomics X-ray crystallography Yeast |
title | In Silico Discovery of 5′-Modified 7‑Deoxy-7-ethynyl-4′-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor |
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