{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:43:07Z","timestamp":1793378587724,"version":"4.5.0"},"reference-count":44,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic & Medicinal Chemistry Letters"],"published-print":{"date-parts":[[2022,12]]},"DOI":"10.1016\/j.bmcl.2022.129016","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T02:53:44Z","timestamp":1664765624000},"page":"129016","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":89,"special_numbering":"C","title":["A first-in-class clinical G-quadruplex-targeting drug. The bench-to-bedside translation of the fluoroquinolone QQ58 to CX-5461 (Pidnarulex)"],"prefix":"10.1016","volume":"77","author":[{"given":"Hong","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence H.","family":"Hurley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmcl.2022.129016_b0005","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1021\/jm00129a001","article-title":"DNA and associated targets for drug design","volume":"32","author":"Hurley","year":"1989","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0010","first-page":"293","article-title":"Untersuchungen \u00fcber die Guanyls\u00e4ure","volume":"26","author":"Bang","year":"1910","journal-title":"Biochem Z"},{"key":"10.1016\/j.bmcl.2022.129016_b0015","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1073\/pnas.48.12.2013","article-title":"Helix formation by guanylic acid","volume":"48","author":"Gellert","year":"1962","journal-title":"PNAS"},{"key":"10.1016\/j.bmcl.2022.129016_b0020","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/334364a0","article-title":"Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis","volume":"334","author":"Sen","year":"1988","journal-title":"Nature"},{"key":"10.1016\/j.bmcl.2022.129016_b0025","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/342825a0","article-title":"Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops","volume":"342","author":"Sundquist","year":"1989","journal-title":"Nature"},{"key":"10.1016\/j.bmcl.2022.129016_b0030","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/350718a0","article-title":"Inhibition of telomerase by G-quartet DNA structures","volume":"350","author":"Zahler","year":"1991","journal-title":"Nature"},{"key":"10.1016\/j.bmcl.2022.129016_b0035","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1021\/jm970199z","article-title":"Inhibition of human telomerase by a G-quadruplex-interactive compound","volume":"40","author":"Sun","year":"1997","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0040","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1093\/nar\/26.5.1167","article-title":"DNA tetraplex formation in the control region of c-myc","volume":"26","author":"Simonsson","year":"1998","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.bmcl.2022.129016_b0045","doi-asserted-by":"crossref","first-page":"11593","DOI":"10.1073\/pnas.182256799","article-title":"Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription","volume":"99","author":"Siddiqui-Jain","year":"2002","journal-title":"PNAS"},{"key":"10.1016\/j.bmcl.2022.129016_b0050","first-page":"103","article-title":"Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects","volume":"1","author":"Duan","year":"2001","journal-title":"Mol Cancer Ther"},{"key":"10.1016\/j.bmcl.2022.129016_b0055","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1158\/0008-5472.CAN-10-1728","article-title":"Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth","volume":"71","author":"Drygin","year":"2011","journal-title":"Cancer Res"},{"key":"10.1016\/j.bmcl.2022.129016_b0060","doi-asserted-by":"crossref","first-page":"14432","DOI":"10.1038\/ncomms14432","article-title":"CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1\/2 deficient tumours","volume":"8","author":"Xu","year":"2017","journal-title":"Nat Commun"},{"key":"10.1016\/j.bmcl.2022.129016_b0065","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1158\/2159-8290.CD-18-1455","article-title":"First-in-human RNA polymerase I transcription inhibitor CX-5461 in patients with advanced hematologic cancers: results of a phase I dose-escalation study","volume":"9","author":"Khot","year":"2019","journal-title":"Cancer Discov."},{"key":"10.1016\/j.bmcl.2022.129016_b0070","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.1073\/pnas.1921649117","article-title":"The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning","volume":"117","author":"Bruno","year":"2020","journal-title":"PNAS"},{"key":"10.1016\/j.bmcl.2022.129016_b0075","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.cell.2020.05.040","article-title":"A genetic map of the response to DNA damage in human cells","volume":"182","author":"Olivieri","year":"2020","journal-title":"Cell"},{"key":"10.1016\/j.bmcl.2022.129016_b0080","doi-asserted-by":"crossref","unstructured":"Bossaert M, Pipier A, Riou JF, et al. Transcription-associated topoisomerase 2\u03b1 (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands. eLife. 2021;10.","DOI":"10.7554\/eLife.65184"},{"key":"10.1016\/j.bmcl.2022.129016_b0085","doi-asserted-by":"crossref","first-page":"6468","DOI":"10.1038\/s41467-021-26640-x","article-title":"The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma","volume":"12","author":"Pan","year":"2021","journal-title":"Nat Commun"},{"key":"10.1016\/j.bmcl.2022.129016_b0090","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1038\/s41467-022-31199-2","article-title":"Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies","volume":"13","author":"Hilton","year":"2022","journal-title":"Nat Commun"},{"key":"10.1016\/j.bmcl.2022.129016_b0095","doi-asserted-by":"crossref","first-page":"9640","DOI":"10.1021\/ja404868t","article-title":"G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells","volume":"135","author":"McLuckie","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2022.129016_b0100","unstructured":"Hilton J, Gelmon K, Cescon D, et al. CCTG IND.231: A phase I trial evaluating CX-5461, a novel first-in-class G-quadruplex stabilizer in patients with advanced solid tumours enriched for DNA-repair deficiencies. San Antonio Breast Cancer Symposium. San Antonio, Texas; 2019."},{"key":"10.1016\/j.bmcl.2022.129016_b0105","doi-asserted-by":"crossref","first-page":"8902","DOI":"10.1021\/ja002179j","article-title":"Selective interactions of cationic porphyrins with G-quadruplex structures","volume":"123","author":"Han","year":"2001","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2022.129016_b0110","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1021\/ja973792e","article-title":"Cationic porphyrins as telomerase inhibitors: the interaction of tetra(n-methyl-4-pyridyl)porphine with quadruplex DNA","volume":"120","author":"Wheelhouse","year":"1998","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2022.129016_b0115","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0163-7258(99)00068-6","article-title":"G-quadruplexes as targets for drug design","volume":"85","author":"Hurley","year":"2000","journal-title":"Pharmacol Ther"},{"key":"10.1016\/j.bmcl.2022.129016_b0120","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1146\/annurev.bi.65.070196.003223","article-title":"DNA topoisomerases","volume":"65","author":"Wang","year":"1996","journal-title":"Annu Rev Biochem"},{"key":"10.1016\/j.bmcl.2022.129016_b0125","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0167-4781(98)00128-6","article-title":"Investigating the biological functions of DNA topoisomerases in eukaryotic cells","volume":"1400","author":"Nitiss","year":"1998","journal-title":"Biochim Biophys Acta, Mol Cell Biol Lipids"},{"key":"10.1016\/j.bmcl.2022.129016_b0130","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0304-3835(97)00269-3","article-title":"New quinolones, ofloxacin and levofloxacin, inhibit telomerase activity in transitional cell carcinoma cell lines","volume":"119","author":"Yamakuchi","year":"1997","journal-title":"Cancer Lett"},{"key":"10.1016\/j.bmcl.2022.129016_b0135","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1021\/jm980265c","article-title":"Design of new topoisomerase II inhibitors based upon a quinobenzoxazine self-assembly model","volume":"41","author":"Zeng","year":"1998","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0140","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/jhet.5570240228","article-title":"Synthesis of 4-oxo-4H-quino-[2,3,4\u2013i, j][1,4]-benoxazine-5-carboxylic acid derivatives","volume":"24","author":"Chu","year":"1987","journal-title":"J Heterocycl Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0145","doi-asserted-by":"crossref","first-page":"4976","DOI":"10.1016\/S0021-9258(19)70730-3","article-title":"Decatenation of kinetoplast DNA by topoisomerases","volume":"255","author":"Marini","year":"1980","journal-title":"J Biol Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0150","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/0003-2697(86)90267-8","article-title":"A quantitative decatenation assay for type II topoisomerases","volume":"156","author":"Sahai","year":"1986","journal-title":"Anal Biochem"},{"key":"10.1016\/j.bmcl.2022.129016_b0155","doi-asserted-by":"crossref","first-page":"28100","DOI":"10.1074\/jbc.M402119200","article-title":"Dissecting the cell-killing mechanism of the topoisomerase II-targeting drug ICRF-193","volume":"279","author":"Oestergaard","year":"2004","journal-title":"J Biol Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0160","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1093\/nar\/27.2.537","article-title":"A DNA polymerase stop assay for G-quadruplex-interactive compounds","volume":"27","author":"Han","year":"1999","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.bmcl.2022.129016_b0165","doi-asserted-by":"crossref","first-page":"20958","DOI":"10.1074\/jbc.271.34.20958","article-title":"The development and use of a DNA polymerase arrest assay for the evaluation of parameters affecting intrastrand tetraplex formation","volume":"271","author":"Weitzmann","year":"1996","journal-title":"J Biol Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0170","doi-asserted-by":"crossref","first-page":"23622","DOI":"10.1074\/jbc.M109.018028","article-title":"Identification and characterization of nucleolin as a c-myc G-quadruplex-binding protein","volume":"284","author":"Gonz\u00e1lez","year":"2009","journal-title":"J Biol Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0175","unstructured":"Jin CH, Rice WG, Siddiqui-Jain A. In vivo efficacy of CX-3543, a novel c-Myc oncogene inhibitor. 95th Annual Meeting, Am. Assoc. Cancer Res.. Abstr. LB\u2010243. Orlando, Florida; 2004."},{"key":"10.1016\/j.bmcl.2022.129016_b0180","series-title":"Substituted quinobenzoxazine analogs and methods of using thereof","author":"Whitten","year":"2009"},{"key":"10.1016\/j.bmcl.2022.129016_b0185","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1177\/1947601910377493","article-title":"Targeting MYC expression through G-quadruplexes","volume":"1","author":"Brooks","year":"2010","journal-title":"Genes Cancer"},{"key":"10.1016\/j.bmcl.2022.129016_b0190","doi-asserted-by":"crossref","first-page":"7653","DOI":"10.1158\/0008-5472.CAN-09-1304","article-title":"Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis","volume":"69","author":"Drygin","year":"2009","journal-title":"Cancer Res"},{"key":"10.1016\/j.bmcl.2022.129016_b0195","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.molcel.2015.12.004","article-title":"Targeting BRCA1 and BRCA2 deficiencies with G-quadruplex-interacting compounds","volume":"61","author":"Zimmer","year":"2016","journal-title":"Mol Cell"},{"key":"10.1016\/j.bmcl.2022.129016_b0200","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1021\/jm900055s","article-title":"The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression","volume":"52","author":"Sun","year":"2009","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0205","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1073\/pnas.1810409116","article-title":"DNA damage and genome instability by G-quadruplex ligands are mediated by R loops in human cancer cells","volume":"116","author":"De Magis","year":"2019","journal-title":"PNAS"},{"key":"10.1016\/j.bmcl.2022.129016_b0210","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.2174\/0929867325666171229132619","article-title":"The interplay between G-quadruplex and transcription","volume":"26","author":"Kim","year":"2019","journal-title":"Curr Med Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0215","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.trechm.2019.07.002","article-title":"The structure and function of DNA G-quadruplexes","volume":"2","author":"Spiegel","year":"2020","journal-title":"Trends Chem"},{"key":"10.1016\/j.bmcl.2022.129016_b0220","doi-asserted-by":"crossref","DOI":"10.3390\/ph14020096","article-title":"The i-motif as a molecular target: more than a complementary DNA secondary structure","volume":"14","author":"Brown","year":"2021","journal-title":"Pharmaceuticals (Basel)"}],"container-title":["Bioorganic & Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X22004929?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X22004929?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T07:45:51Z","timestamp":1760773551000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X22004929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12]]},"references-count":44,"alternative-id":["S0960894X22004929"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2022.129016","relation":{},"ISSN":["0960-894X"],"issn-type":[{"value":"0960-894X","type":"print"}],"subject":[],"published":{"date-parts":[[2022,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"A first-in-class clinical G-quadruplex-targeting drug. The bench-to-bedside translation of the fluoroquinolone QQ58 to CX-5461 (Pidnarulex)","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2022.129016","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"129016"}}