{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T07:03:50Z","timestamp":1782889430792,"version":"3.54.5"},"reference-count":73,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Competitiveness, Entrepreneurship and Innovation","award":["NSRF 2014-2020"],"award-info":[{"award-number":["NSRF 2014-2020"]}]},{"name":"Greece and the European Union"},{"name":"Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediates histone H3 lysine 27 trimethylation (H3K27me3), an epigenetic modification associated with transcriptional repression. EZH2 inhibitors (EZH2is) gained attention after the first-in-class drug Tazemetostat received FDA approval for treating epithelioid sarcoma. Preclinical studies suggest that EZH2is could be effective against melanoma, but their general inability to cross the blood\u2013brain barrier (BBB), among others, limits the treatment of secondary brain metastases. Based on these limitations, we designed SG-8, a novel compound derived from TDI-6118 (a known brain-penetrant EZH2i). In silico docking predicted that SG-8 may exhibit high affinity for EZH2 as well as for another PRC2 subunit, Embryonic Ectoderm Development (EED). In addition, in vitro PAMPA assays suggested passive BBB permeability of SG-8. In cell-based assays, SG-8 and the structurally related EZH2i PF-06726304 displayed lower cytotoxicity than Tazemetostat in both primary (A375) and metastatic (Colo-679) human melanoma cells. Western blot analysis showed that SG-8 and PF-06726304 markedly reduced EED protein levels and, to a lesser extent, EZH2 levels, without affecting total H3K27me3, consistent with preserved canonical PRC2 activity. Instead, treatment with both compounds\u2014most prominently SG-8\u2014was associated with reduced phosphorylation levels of EZH2 (Ser21) and its upstream regulator Akt (Ser473), suggesting that modulation of the Akt\u2013EZH2 signaling axis may at least partially contribute to their anti-melanoma activity.<\/jats:p>","DOI":"10.3390\/ijms27062647","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:36:48Z","timestamp":1773423408000},"page":"2647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biological Evaluation of a Novel Compound with Predicted EZH2 and EED Binding Against Human Malignant Melanoma Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2883-3579","authenticated-orcid":false,"given":"Sergei","family":"Gorbunov","sequence":"first","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6195-6570","authenticated-orcid":false,"given":"Sotiris","family":"Kyriakou","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2052-8470","authenticated-orcid":false,"given":"Ioannis","family":"Anestopoulos","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahzaib","family":"Khoso","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0632-5618","authenticated-orcid":false,"given":"Marcello","family":"Manfredi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy"},{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3241-8615","authenticated-orcid":false,"given":"Rodrigo","family":"Franco","sequence":"additional","affiliation":[{"name":"Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"},{"name":"Department of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0913-4315","authenticated-orcid":false,"given":"Aglaia","family":"Pappa","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1450-3552","authenticated-orcid":false,"given":"Mihalis I.","family":"Panayiotidis","sequence":"additional","affiliation":[{"name":"Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"},{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS 39762, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature02625","article-title":"Epigenetics in human disease and prospects for epigenetic therapy","volume":"429","author":"Egger","year":"2004","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/nbt.1685","article-title":"Epigenetic modifications and human disease","volume":"28","author":"Portela","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/path.1024","article-title":"Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours","volume":"196","author":"Esteller","year":"2002","journal-title":"J. Pathol."},{"key":"ref_4","first-page":"277","article-title":"The roles of histone modifications in tumorigenesis and associated inhibitors in cancer therapy","volume":"2","author":"Yang","year":"2022","journal-title":"J. Natl. Cancer Cent."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/s41397-019-0138-5","article-title":"Cancer\u2019s epigenetic drugs: Where are they in the cancer medicines?","volume":"20","author":"Ghasemi","year":"2020","journal-title":"Pharmacogenomics J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.semcancer.2020.12.006","article-title":"Progress and promises of epigenetic drugs and epigenetic diets in cancer prevention and therapy: A clinical update","volume":"83","author":"Mondal","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1080\/14737140.2019.1552139","article-title":"Cancer epigenetics and the potential of epigenetic drugs for treating solid tumors","volume":"19","author":"Liu","year":"2019","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12460","DOI":"10.1021\/acs.jmedchem.0c00830","article-title":"Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight","volume":"63","author":"Ho","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s40265-020-01288-x","article-title":"Tazemetostat: First Approval","volume":"80","author":"Hoy","year":"2020","journal-title":"Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7922","DOI":"10.1073\/pnas.1303800110","article-title":"Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2","volume":"110","author":"Knutson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41416-019-0615-2","article-title":"Engaging chromatin: PRC2 structure meets function","volume":"122","author":"Chammas","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.molcel.2019.03.011","article-title":"Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation","volume":"74","author":"Laugesen","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/nchembio.1084","article-title":"A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells","volume":"8","author":"Knutson","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1002\/tcr.201800091","article-title":"Six Years (2012\u20132018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds","volume":"18","author":"Fioravanti","year":"2018","journal-title":"Chem. Rec."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s12032-023-02025-6","article-title":"The roles of EZH2 in cancer and its inhibitors","volume":"40","author":"Liu","year":"2023","journal-title":"Med. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11384","DOI":"10.1038\/ncomms11384","article-title":"Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance","volume":"7","author":"Brooun","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9928","DOI":"10.1021\/acs.jmedchem.6b01315","article-title":"Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin- 3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas","volume":"59","author":"Vaswani","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8306","DOI":"10.1021\/acs.jmedchem.6b00515","article-title":"Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors","volume":"59","author":"Kung","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_19","unstructured":"Edwards, M.P., Kumpf, R.A., Kung, P.-P., McAlpine, I.J., Ninkovic, S., Rui, E.Y., Sutton, S.C., Tatlock, J.H., Wythes, M.J., and Zehnder, L.R. (2014). Aryl and heteroaryl fused lactams. (WO 2014\/097041 A1), Patent."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1021\/acs.jmedchem.7b01375","article-title":"Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2(EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-isoquinolin-1(2H)-one (PF-06821497)","volume":"61","author":"Kung","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"32646","DOI":"10.18632\/oncotarget.5066","article-title":"Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors","volume":"6","author":"Baker","year":"2015","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/onc.2015.114","article-title":"Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors","volume":"35","author":"Gibaja","year":"2016","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1182\/blood-2017-08-804344","article-title":"Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas","volume":"131","author":"Bisserier","year":"2018","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1182\/blood-2014-06-581082","article-title":"Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia","volume":"125","author":"Xu","year":"2015","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1007\/s40265-022-01800-5","article-title":"Valemetostat Tosilate: First Approval","volume":"82","author":"Keam","year":"2022","journal-title":"Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11774","DOI":"10.1021\/acs.jmedchem.1c00226","article-title":"Polycomb Repressive Complex 2 Modulation through the Development of EZH2\u2013EED Interaction Inhibitors and EED Binders","volume":"64","author":"Tomassi","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1039\/D1MD00274K","article-title":"An overview of the development of EED inhibitors to disable the PRC2 function","volume":"13","author":"Liu","year":"2022","journal-title":"RSC Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/S0140-6736(13)60802-8","article-title":"Cutaneous melanoma","volume":"383","author":"Eggermont","year":"2014","journal-title":"Lancet"},{"key":"ref_29","unstructured":"(2025, September 23). National Cancer Institute: Melanoma of the Skin-Cancer Stat Facts, Available online: https:\/\/seer.cancer.gov\/statfacts\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41392-021-00827-6","article-title":"Signal pathways of melanoma and targeted therapy","volume":"6","author":"Guo","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6051","DOI":"10.1038\/ncomms7051","article-title":"The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors","volume":"6","author":"Zingg","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.celrep.2017.07.007","article-title":"The Histone Methyltransferase Ezh2 Controls Mechanisms of Adaptive Resistance to Tumor Immunotherapy","volume":"20","author":"Zingg","year":"2017","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27023","DOI":"10.18632\/oncotarget.4809","article-title":"Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes","volume":"6","author":"Tiffen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"115493","DOI":"10.1016\/j.bcp.2023.115493","article-title":"Pharmacological inhibition of EZH2 by ZLD1039 suppresses tumor growth and pulmonary metastasis in melanoma cells in vitro and in vivo","volume":"210","author":"Zhu","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Anestopoulos, I., Paraskevaidis, I., Kyriakou, S., Giova, L.E., Trafalis, D.T., Botaitis, S., Franco, R., Pappa, A., and Panayiotidis, M.I. (2024). Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052745"},{"key":"ref_36","first-page":"4655","article-title":"Recent Trends in Epidemiology of Brain Metastases: An Overview","volume":"32","author":"Tabouret","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nm.4293","article-title":"EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas","volume":"23","author":"Mohammad","year":"2017","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nm.4296","article-title":"Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas","volume":"23","author":"Piunti","year":"2017","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.cell.2020.04.047","article-title":"Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma","volume":"181","author":"Michealraj","year":"2020","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"iii1","DOI":"10.1093\/neuonc\/nov061.1","article-title":"AT-01. Therapeutic targeting of INI1 deficiency in pediatric ATRT: A pre-clinical study utilizing patient derived orthotopic xenograft (PDOX) models","volume":"17","author":"Lindsay","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10551","DOI":"10.1200\/JCO.2018.36.15_suppl.10551","article-title":"Pediatric preclinical testing consortium evaluation of the EZH2 inhibitor tazemetostat in orthotopic PDX models of pediatric brain tumors","volume":"36","author":"Li","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1002\/ijc.29566","article-title":"ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors","volume":"137","author":"Zhang","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1021\/acsmedchemlett.1c00448","article-title":"A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors","volume":"13","author":"Liang","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41586-023-05905-z","article-title":"Computational approaches streamlining drug discovery","volume":"616","author":"Sadybekov","year":"2023","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1016\/j.drudis.2020.09.021","article-title":"Recent progress on cheminformatics approaches to epigenetic drug discovery","volume":"25","author":"Sessions","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Prado-Romero, D.L., G\u00f3mez-Garc\u00eda, A., Cedillo-Gonz\u00e1lez, R., Villegas-Quintero, H., Avellaneda-Tamayo, J.F., L\u00f3pez-L\u00f3pez, E., Sald\u00edvar-Gonz\u00e1lez, F.I., Ch\u00e1vez-Hern\u00e1ndez, A.L., and Medina-Franco, J.L. (2023). Consensus docking aid to model the activity of an inhibitor of DNA methyltransferase 1 inspired by de novo design. Front. Drug Discov., 3.","DOI":"10.3389\/fddsv.2023.1261094"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41392-024-02039-0","article-title":"Epigenetics-targeted drugs: Current paradigms and future challenges","volume":"9","author":"Dai","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1002\/cmdc.201600182","article-title":"A BOILED-Egg to Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules","volume":"11","author":"Daina","year":"2016","journal-title":"Chem. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"Swiss ADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nrd1549","article-title":"Docking and scoring in virtual screening for drug discovery: Methods and applications","volume":"3","author":"Kitchen","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1021\/ci100436p","article-title":"FRED Pose Prediction and Virtual Screening Accuracy","volume":"51","author":"McGann","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1021\/ci990307l","article-title":"Prediction of physicochemical parameters by atomic contributions","volume":"39","author":"Wildman","year":"1999","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1021\/jm000942e","article-title":"Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties","volume":"43","author":"Ertl","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1021\/jm001020e","article-title":"High-throughput permeability pH profile and high-throughput alkane\/water log P with artificial membranes","volume":"44","author":"Wohnsland","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0223-5234(03)00012-6","article-title":"High throughput artificial membrane permeability assay for blood\u2013brain barrier","volume":"38","author":"Di","year":"2003","journal-title":"Eur. J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s10637-019-00809-0","article-title":"Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma","volume":"38","author":"Kyriakou","year":"2020","journal-title":"Investig. New Drugs"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1007\/s10637-021-01127-0","article-title":"Benzyl and phenethyl isothiocyanates as promising epigenetic drug compounds by modulating histone acetylation and methylation marks in malignant melanoma","volume":"39","author":"Mitsiogianni","year":"2021","journal-title":"Investig. New Drugs"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1126\/science.1118947","article-title":"Akt-Mediated Phosphorylation of EZH2 Suppresses Methylation of Lysine 27 in Histone H3","volume":"310","author":"Cha","year":"2005","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"8194","DOI":"10.1021\/acs.jmedchem.0c02261","article-title":"Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction","volume":"64","author":"Du","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9512","DOI":"10.1021\/jm501230c","article-title":"Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2","volume":"57","author":"Kong","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13049","DOI":"10.18632\/oncotarget.3790","article-title":"Wedelolactone disrupts the interaction of EZH2-EED complex and inhibits PRC2-dependent cancer","volume":"6","author":"Chen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Anestopoulos, I., Sfakianos, A.P., Franco, R., Chlichlia, K., Panayiotidis, M.I., Kroll, D.J., and Pappa, A. (2017). A novel role of silibinin as a putative epigenetic modulator in human prostate carcinoma. Molecules, 22.","DOI":"10.3390\/molecules22010062"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6873","DOI":"10.7150\/thno.49235","article-title":"Pharmacological inhibition of noncanonical EED-EZH2 signaling overcomes chemoresistance in prostate cancer","volume":"11","author":"Li","year":"2021","journal-title":"Theranostics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/s41416-023-02359-y","article-title":"Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models","volume":"129","author":"Li","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1111\/cas.14840","article-title":"The non-canonical role of EZH2 in cancer","volume":"112","author":"Huang","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Zimmerman, S.M., Lin, P.N., and Souroullas, G.P. (2023). Non-canonical functions of EZH2 in cancer. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1233953"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.ccr.2013.04.008","article-title":"Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells","volume":"23","author":"Kim","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF Chimera X: Meeting modern challenges in visualization and analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"key":"ref_73","first-page":"22","article-title":"Molecular interaction analysis and visualization of protein-ligand docking using Biovia Discovery Studio Visualizer","volume":"2","author":"Baroroh","year":"2023","journal-title":"Indones. J. Comput. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2647\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:43:28Z","timestamp":1773751408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2647"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":73,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062647"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062647","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,13]]}}}