{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:26:59Z","timestamp":1786724819579,"version":"build-2736575974"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006264","name":"RIKEN","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23ama121053"],"award-info":[{"award-number":["JP23ama121053"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23fk0210100h0003"],"award-info":[{"award-number":["JP23fk0210100h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24jm0210092s0104"],"award-info":[{"award-number":["JP24jm0210092s0104"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K07349"],"award-info":[{"award-number":["JP20K07349"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K10088"],"award-info":[{"award-number":["JP24K10088"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJNX25E3"],"award-info":[{"award-number":["JPMJNX25E3"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>MYCN is a key oncogenic driver in hepatocellular carcinoma (HCC) and a therapeutic challenge due to the historical undruggability of MYC transcription factors (TFs). Using a high-throughput MYCN promoter\u2013luciferase reporter, we identified PhiKan 083 (PK83), a small molecule previously recognized as a mutant p53 activator, that dose-dependently suppresses MYCN expression in HCC cells. PK83 impaired the proliferation and survival of MYCN-high HCC cells, inducing DNA damage, apoptosis, and loss of clonogenic and spheroid growth potential, while sparing MYCN-low HCC cells and normal hepatocytes. Structure\u2013activity analysis revealed that polar, hydrogen-bond-capable substituents on PK83\u2019s tricyclic scaffold are critical for its activity. Although PK83 broadly activates p53 signaling, its cytotoxicity in MYCN-high cells is not strictly dependent on intact p53, as confirmed in p53-knockout systems. Transcriptome profiling and pathway analysis demonstrated robust suppression of MYC\/MYCN targets along with modulation of pathways linked to stress, differentiation, and metabolism. In primary HCC tumors, PK83-downregulated TFs, including oncogenic TFs ZMIZ1 and TARBP1, positively correlated with MYCN, whereas upregulated stress-responsive TFs ATF3 and FOSL2 showed a negative correlation. These findings suggest that PK83 suppresses MYCN expression and preferentially affects MYCN-high HCC cells in a p53-independent manner, warranting further preclinical investigation of PK83 and related compounds in MYCN-associated cancers.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00044","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T13:46:13Z","timestamp":1784382373000},"page":"2225-2233","source":"Crossref","is-referenced-by-count":0,"title":["PhiKan 083 Inhibits MYCN Expression in Liver Cancer\nCells Independent of p53 Pathways"],"prefix":"10.1021","volume":"9","author":[{"given":"Yali","family":"Xu","sequence":"first","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , , Tsurumi-ku, ,","place":["Yokohama, Japan, 2300045"]},{"name":"Medical School of Nanjing University , , Gulou, ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hricha","family":"Mishra","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , , Tsurumi-ku, ,","place":["Yokohama, Japan, 2300045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Takahashi","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , , Tsurumi-ku, ,","place":["Yokohama, Japan, 2300045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Nishimura","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , , Tsurumi-ku, ,","place":["Yokohama, Japan, 2300045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Suenaga","sequence":"additional","affiliation":[{"name":"Chiba Cancer Center Research Institute , , Chuo-ku, ,","place":["Chiba, Japan, 2608717"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4218-0321","authenticated-orcid":true,"given":"Wenkui","family":"Yu","sequence":"additional","affiliation":[{"name":"Medical School of Nanjing University , , Gulou, ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4975-1812","authenticated-orcid":true,"given":"Yoshitaka","family":"Hippo","sequence":"additional","affiliation":[{"name":"Chiba Cancer Center Research Institute , , Chuo-ku, ,","place":["Chiba, Japan, 2608717"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harukazu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , , Tsurumi-ku, ,","place":["Yokohama, Japan, 2300045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0110-6849","authenticated-orcid":true,"given":"Xian-Yang","family":"Qin","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , , Tsurumi-ku, ,","place":["Yokohama, Japan, 2300045"]},{"name":"Gifu University Graduate School of Medicine , , Yanagido, ,","place":["Gifu, Japan, 5011194"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"issue":"3","key":"2026081411071626200_cit1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer\nStatistics\n2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for\n36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"Ca-Cancer J. Clin."},{"issue":"15","key":"2026081411071626200_cit2","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular\nCarcinoma","volume":"380","author":"Villanueva","year":"2019","journal-title":"N. Engl. J. Med."},{"issue":"1","key":"2026081411071626200_cit3","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat.\nRev. Dis. Primers"},{"issue":"9","key":"2026081411071626200_cit4","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1111\/liv.12818","article-title":"Global patterns of\nhepatocellular\ncarcinoma management from diagnosis to death: the BRIDGE Study","volume":"35","author":"Park","year":"2015","journal-title":"Liver Int."},{"issue":"4","key":"2026081411071626200_cit5","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"SHARP Investigators\nStudy Group. Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"issue":"20","key":"2026081411071626200_cit6","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"IMbrave150 Investigators. Atezolizumab\nplus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"issue":"12","key":"2026081411071626200_cit7","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1001\/jamaoncol.2017.3055","article-title":"The Burden of Primary Liver Cancer and Underlying Etiologies\nFrom 1990 to 2015 at the Global, Regional, and National Level: Results\nFrom the Global Burden of Disease Study 2015","volume":"3","author":"Global Burden of Disease Liver Cancer","year":"2017","journal-title":"JAMA Oncol."},{"issue":"1\u20132","key":"2026081411071626200_cit8","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0304-3835(03)00096-X","article-title":"The MYCN oncoprotein as a drug development\ntarget","volume":"197","author":"Lu","year":"2003","journal-title":"Cancer Lett."},{"issue":"2","key":"2026081411071626200_cit9","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.canlet.2010.01.015","article-title":"MYCN oncoprotein\ntargets and their therapeutic potential","volume":"293","author":"Bell","year":"2010","journal-title":"Cancer\nLett."},{"issue":"3","key":"2026081411071626200_cit10","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/ijc.34893","article-title":"Serum MYCN\nas a predictive biomarker of prognosis and therapeutic response in\nthe prevention of hepatocellular carcinoma recurrence","volume":"155","author":"Qin","year":"2024","journal-title":"Int. J. Cancer"},{"issue":"19","key":"2026081411071626200_cit11","doi-asserted-by":"publisher","first-page":"4969","DOI":"10.1073\/pnas.1802279115","article-title":"Prevention\nof hepatocellular carcinoma by targeting MYCN-positive liver cancer\nstem cells with acyclic retinoid","volume":"115","author":"Qin","year":"2018","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"6","key":"2026081411071626200_cit12","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1158\/1541-7786.MCR-13-0536","article-title":"The N-myc\nOncogene: Maximizing its Targets, Regulation, and Therapeutic Potential","volume":"12","author":"Beltran","year":"2014","journal-title":"Mol. Cancer Res."},{"issue":"3","key":"2026081411071626200_cit13","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1111\/cas.14292","article-title":"MicroRNA-493\u20135p-mediated\nrepression of the MYCN oncogene inhibits hepatic cancer cell growth\nand invasion","volume":"111","author":"Yasukawa","year":"2020","journal-title":"Cancer Sci."},{"key":"2026081411071626200_cit14","doi-asserted-by":"publisher","first-page":"791","DOI":"10.3389\/fonc.2020.00791","article-title":"Beyond\nthe Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in\nCancer Cells","volume":"10","author":"Yoshida","year":"2020","journal-title":"Front. Oncol."},{"issue":"1","key":"2026081411071626200_cit15","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/s41419-020-2257-y","article-title":"Lipid desaturation-associated endoplasmic\nreticulum stress regulates MYCN gene expression in hepatocellular\ncarcinoma cells","volume":"11","author":"Qin","year":"2020","journal-title":"Cell Death Dis."},{"key":"2026081411071626200_cit16","doi-asserted-by":"publisher","first-page":"1486671","DOI":"10.3389\/fonc.2025.1486671","article-title":"A high-throughput\nscreening platform\nto identify MYCN expression inhibitors for liver cancer therapy","volume":"15","author":"Xu","year":"2025","journal-title":"Front. Oncol."},{"issue":"6","key":"2026081411071626200_cit17","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1016\/j.cell.2017.08.028","article-title":"Putting p53 in Context","volume":"170","author":"Kastenhuber","year":"2017","journal-title":"Cell"},{"issue":"1","key":"2026081411071626200_cit18","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.ajpath.2010.11.010","article-title":"Proteasome inhibitors induce p53-independent apoptosis\nin human cancer cells","volume":"178","author":"Pandit","year":"2011","journal-title":"Am. J. Pathol."},{"issue":"10","key":"2026081411071626200_cit19","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/nrc1455","article-title":"Post-translational modification of p53 in tumorigenesis","volume":"4","author":"Bode","year":"2004","journal-title":"Nat. Rev. Cancer"},{"issue":"8779","key":"2026081411071626200_cit20","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1016\/0140-6736(91)92236-u","article-title":"p53 mutation in hepatocellular carcinoma after aflatoxin\nexposure","volume":"338","author":"Bressac","year":"1991","journal-title":"The Lancet"},{"issue":"2","key":"2026081411071626200_cit21","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41573-022-00571-8","article-title":"Drugging p53 in cancer:\none protein, many targets","volume":"22","author":"Hassin","year":"2023","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"30","key":"2026081411071626200_cit22","doi-asserted-by":"publisher","first-page":"10360","DOI":"10.1073\/pnas.0805326105","article-title":"Targeted rescue of a destabilized\nmutant of p53 by an in silico screened drug","volume":"105","author":"Boeckler","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"8","key":"2026081411071626200_cit23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2521923123","article-title":"Oncogenic function\nand transcriptional dynamics of\nMYCN in liver tumorigenesis","volume":"123","author":"Qin","year":"2026","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"7391","key":"2026081411071626200_cit24","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer\nCell Line Encyclopedia enables predictive modelling of anticancer\ndrug sensitivity","volume":"483","author":"Barretina","year":"2012","journal-title":"Nature"},{"key":"2026081411071626200_cit25","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1021\/acschembio.5c00675","article-title":"Chemical Screening of RIKEN Natural\nProducts Depository Identified a MYCN Expression Inhibitor Partially\nthrough HGF-MET Signaling Pathway","volume":"21","author":"Xu","year":"2026","journal-title":"ACS Chem.\nBiol."},{"issue":"41","key":"2026081411071626200_cit26","doi-asserted-by":"publisher","first-page":"15056","DOI":"10.1073\/pnas.0607286103","article-title":"Structural\nbasis for understanding\noncogenic p53 mutations and designing rescue drugs","volume":"103","author":"Joerger","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081411071626200_cit27","doi-asserted-by":"publisher","first-page":"1333447","DOI":"10.3389\/fphar.2023.1333447","article-title":"Targeting p53 misfolding conundrum by stabilizing agents\nand their analogs in breast cancer therapy: a comprehensive computational\nanalysis","volume":"14","author":"Haq","year":"2024","journal-title":"Front. Pharmacol."},{"issue":"1","key":"2026081411071626200_cit28","doi-asserted-by":"publisher","first-page":"6821","DOI":"10.1038\/s41467-025-62131-z","article-title":"Impairing the interaction between Erg11 and cytochrome P450 reductase\nNcp1 enhances azoles\u2019 antifungal activities","volume":"16","author":"Li","year":"2025","journal-title":"Nat. Commun."},{"issue":"5","key":"2026081411071626200_cit29","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.cell.2009.11.007","article-title":"Epithelial-mesenchymal\ntransitions in development and disease","volume":"139","author":"Thiery","year":"2009","journal-title":"Cell"},{"issue":"12","key":"2026081411071626200_cit30","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.tcb.2011.06.005","article-title":"Epithelial organization, cell polarity and tumorigenesis","volume":"21","author":"McCaffrey","year":"2011","journal-title":"Trends Cell Biol."},{"issue":"12","key":"2026081411071626200_cit31","doi-asserted-by":"publisher","first-page":"100264","DOI":"10.1016\/j.labinv.2023.100264","article-title":"ZMIZ1 Upregulation\nof TET3-Mediated Hydroxymethylation\nInduces M2 Polarization of Kupffer Cells in Hepatocellular Carcinogenesis\nby Mediating Notch1\/c-Myc Signaling","volume":"103","author":"Liu","year":"2023","journal-title":"Lab. Invest."},{"issue":"9","key":"2026081411071626200_cit32","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1038\/s41418-024-01323-4","article-title":"The tRNA Gm18\nmethyltransferase TARBP1 promotes hepatocellular carcinoma progression\nvia metabolic reprogramming of glutamine","volume":"31","author":"Shi","year":"2024","journal-title":"Cell\nDeath Differ."},{"issue":"1","key":"2026081411071626200_cit33","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1186\/s13046-018-0919-8","article-title":"ATF3 inhibits\nthe tumorigenesis and progression of hepatocellular carcinoma cells\nvia upregulation of CYR61 expression","volume":"37","author":"Chen","year":"2018","journal-title":"J. Exp.\nClin. Cancer Res."},{"issue":"1","key":"2026081411071626200_cit34","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/onc.2017.310","article-title":"Atf3 deficiency promotes\ngenome instability and spontaneous tumorigenesis\nin mice","volume":"37","author":"Wang","year":"2018","journal-title":"Oncogene"},{"issue":"11","key":"2026081411071626200_cit35","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/s41419-018-1150-4","article-title":"TXNDC9 promotes\nhepatocellular carcinoma progression by positive\nregulation of MYC-mediated transcriptional network","volume":"9","author":"Chen","year":"2018","journal-title":"Cell Death Dis."},{"issue":"1","key":"2026081411071626200_cit36","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s13046-020-01576-0","article-title":"Hsa_circ_0003998\npromotes epithelial to mesenchymal transition of hepatocellular carcinoma\nby sponging miR-143\u20133p and PCBP1","volume":"39","author":"Song","year":"2020","journal-title":"J.\nExp. Clin. Cancer Res."}],"container-title":["ACS Pharmacology &amp; Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.6c00044","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/8\/2225\/66021386\/acsptsci.6c00044.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/8\/2225\/66021386\/acsptsci.6c00044.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:28:08Z","timestamp":1786721288000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/9\/8\/2225\/5215121\/PhiKan-083-Inhibits-MYCN-Expression-in-Liver"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,18]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,18]]},"published-print":{"date-parts":[[2026,8,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.6c00044","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,18]]}}}