{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T19:53:00Z","timestamp":1785700380807,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,31]]},"group-title":"Biochemistry","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35-CA197569"],"award-info":[{"award-number":["R35-CA197569"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Epigenetic Therapies - New Approaches P50CA254897 Career Enhancement Program"],"award-info":[{"award-number":["Epigenetic Therapies - New Approaches P50CA254897 Career Enhancement Program"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Liz and Eric Lefkofsky Innovation Research Awards"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>COMPASS (Complex of proteins associated with Set1) are highly conserved chromatin regulatory complexes responsible for all methylation marks on histone H3 lysine 4 (H3K4). The COMPASS protein SET1A is upregulated in metastatic breast cancer, and its H3K4 methyltransferase activity promotes metastasis in a palmitic acid diet setting. We identify and characterize FCD-11, a first-in-class small molecule inhibitor of COMPASS activity designed to disrupt the termolecular interface between COMPASS SET domains, ASH2L, and RBBP5. FCD-11 significantly inhibited the H3K4me3 methyltransferase activity of SET1A\/COMPASS and MLL1\/COMPASS in vitro. ChIP-seq and CETSA indicated that FCD-11 selectively inhibits SET1A\/COMPASS activity in mouse embryonic stem cells and breast cancer cell lines. FCD-11 significantly reduced tumor size and extended survival in mouse models of breast cancer. Our findings establish FCD-11 as a potent, COMPASS-specific inhibitor lead compound with preclinical efficacy in breast cancer models and therapeutic potential for cancers with abnormal dependence on SET1A\/COMPASS activity.<\/jats:p>","DOI":"10.64898\/2026.07.30.741768","type":"posted-content","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:55:17Z","timestamp":1785491717000},"source":"Crossref","is-referenced-by-count":0,"title":["FCD-11: A First-in-Class COMPASS Inhibitor in Cancer Therapeutics"],"prefix":"10.64898","author":[{"given":"Zibo","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenal","family":"Karunanidhi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"St John","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rukkia","family":"Liaqat","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Iwanaszko","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Bigas","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eita","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Mineji","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador Aznar","family":"Benitah","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rintaro","family":"Hashizume","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama K.","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Shilatifard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"},{"name":"Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080212250978000_2026.07.30.741768v1.1","doi-asserted-by":"crossref","unstructured":"S. Gold , A. Shilatifard , Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges. J Clin Invest 134, (2024).","DOI":"10.1172\/JCI183391"},{"key":"2026080212250978000_2026.07.30.741768v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-0278-0"},{"key":"2026080212250978000_2026.07.30.741768v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-051710-134100"},{"key":"2026080212250978000_2026.07.30.741768v1.4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609809200"},{"key":"2026080212250978000_2026.07.30.741768v1.5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508312200"},{"key":"2026080212250978000_2026.07.30.741768v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaz4764"},{"key":"2026080212250978000_2026.07.30.741768v1.7","doi-asserted-by":"publisher","DOI":"10.1101\/gad.201327.112"},{"key":"2026080212250978000_2026.07.30.741768v1.8","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01181-13"},{"key":"2026080212250978000_2026.07.30.741768v1.9","doi-asserted-by":"publisher","DOI":"10.1007\/s12038-017-9666-9"},{"key":"2026080212250978000_2026.07.30.741768v1.10","doi-asserted-by":"crossref","unstructured":"J. J. Meeks , A. Shilatifard , Multiple roles for the MLL\/COMPASS family in the epigenetic regulation of gene expression and in cancer. (2017).","DOI":"10.1146\/annurev-cancerbio-050216-034333"},{"key":"2026080212250978000_2026.07.30.741768v1.11","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-14-0389"},{"key":"2026080212250978000_2026.07.30.741768v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.05.018"},{"key":"2026080212250978000_2026.07.30.741768v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04075-0"},{"key":"2026080212250978000_2026.07.30.741768v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1528-1"},{"key":"2026080212250978000_2026.07.30.741768v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.020"},{"key":"2026080212250978000_2026.07.30.741768v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.06.038"},{"key":"2026080212250978000_2026.07.30.741768v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1454"},{"key":"2026080212250978000_2026.07.30.741768v1.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200348200"},{"key":"2026080212250978000_2026.07.30.741768v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.10.013"},{"key":"2026080212250978000_2026.07.30.741768v1.20","doi-asserted-by":"crossref","unstructured":"E. J. Worden , X. Zhang , C. Wolberger , Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome. Elife 9, (2020).","DOI":"10.7554\/eLife.53199"},{"key":"2026080212250978000_2026.07.30.741768v1.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2205691119"},{"key":"2026080212250978000_2026.07.30.741768v1.22","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.06026-11"},{"key":"2026080212250978000_2026.07.30.741768v1.23","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1038\/s41467-019-13550-2","article-title":"Cryo-EM structure of the human MLL1 core complex bound to the nucleosome","volume":"10","year":"2019","journal-title":"Nat Commun"},{"key":"2026080212250978000_2026.07.30.741768v1.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109360108"},{"key":"2026080212250978000_2026.07.30.741768v1.25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr777"},{"key":"2026080212250978000_2026.07.30.741768v1.26","doi-asserted-by":"publisher","DOI":"10.1101\/gad.294744.116"},{"key":"2026080212250978000_2026.07.30.741768v1.27","doi-asserted-by":"publisher","DOI":"10.1101\/gad.303768.117"},{"key":"2026080212250978000_2026.07.30.741768v1.28","doi-asserted-by":"crossref","unstructured":"Z. Zhao et al., Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3\/4-COMPASS epigenetic regulator mutations. J Clin Invest 133, (2023).","DOI":"10.1172\/JCI169993"},{"key":"2026080212250978000_2026.07.30.741768v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1128"},{"key":"2026080212250978000_2026.07.30.741768v1.30","doi-asserted-by":"crossref","unstructured":"L. Zhao et al., DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates. iScience 25, 104948 (2022).","DOI":"10.1016\/j.isci.2022.104948"},{"key":"2026080212250978000_2026.07.30.741768v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23268-9"},{"key":"2026080212250978000_2026.07.30.741768v1.32","doi-asserted-by":"publisher","DOI":"10.1101\/gad.306092.117"},{"key":"2026080212250978000_2026.07.30.741768v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.032"},{"key":"2026080212250978000_2026.07.30.741768v1.34","doi-asserted-by":"crossref","unstructured":"T. Hoshii et al., SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia. Cell Rep 41, 111727 (2022).","DOI":"10.1016\/j.celrep.2022.111727"},{"key":"2026080212250978000_2026.07.30.741768v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.06.002"},{"key":"2026080212250978000_2026.07.30.741768v1.36","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","year":"2021","journal-title":"J Med Chem"},{"key":"2026080212250978000_2026.07.30.741768v1.37","doi-asserted-by":"crossref","first-page":"5317","DOI":"10.1021\/acs.jmedchem.1c02148","article-title":"Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies","volume":"65","year":"2022","journal-title":"J Med Chem"},{"key":"2026080212250978000_2026.07.30.741768v1.38","doi-asserted-by":"crossref","unstructured":"W. Chen et al., Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity. Eur J Med Chem 223, 113677 (2021).","DOI":"10.1016\/j.ejmech.2021.113677"},{"key":"2026080212250978000_2026.07.30.741768v1.39","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00091"},{"key":"2026080212250978000_2026.07.30.741768v1.40","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1002\/ijc.31853","article-title":"Aberrant expression of SETD1A promotes survival and migration of estrogen receptor alpha-positive breast cancer cells","volume":"143","year":"2018","journal-title":"Int J Cancer"},{"key":"2026080212250978000_2026.07.30.741768v1.41","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.7150\/thno.72599","article-title":"SETD1A-SOX2 axis is involved in tamoxifen resistance in estrogen receptor alpha-positive breast cancer cells","volume":"12","year":"2022","journal-title":"Theranostics"},{"key":"2026080212250978000_2026.07.30.741768v1.42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075198"},{"key":"2026080212250978000_2026.07.30.741768v1.43","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00753"},{"key":"2026080212250978000_2026.07.30.741768v1.44","doi-asserted-by":"publisher","DOI":"10.1021\/ci800324m"},{"key":"2026080212250978000_2026.07.30.741768v1.45","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5b00559"},{"key":"2026080212250978000_2026.07.30.741768v1.46","doi-asserted-by":"crossref","unstructured":"H. R. Powell , S. A. Islam , A. David , M. J. E. Sternberg , Phyre2.2: A Community Resource for Template-based Protein Structure Prediction. J Mol Biol 437, 168960 (2025).","DOI":"10.1016\/j.jmb.2025.168960"},{"key":"2026080212250978000_2026.07.30.741768v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-021-03819-2"},{"key":"2026080212250978000_2026.07.30.741768v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAD1011"},{"key":"2026080212250978000_2026.07.30.741768v1.49","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm216"},{"key":"2026080212250978000_2026.07.30.741768v1.50","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt Removes Adapter Sequences From High-Throughput Sequencing Reads","volume":"17","year":"2011","journal-title":"EMBnet.jouornal"},{"key":"2026080212250978000_2026.07.30.741768v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"2026080212250978000_2026.07.30.741768v1.52","doi-asserted-by":"crossref","unstructured":"Y. Zhang et al., Model-based analysis of ChIP-Seq (MACS). Genome Biol 9, R137 (2008).","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"2026080212250978000_2026.07.30.741768v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"2026080212250978000_2026.07.30.741768v1.54","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku365"},{"key":"2026080212250978000_2026.07.30.741768v1.55","unstructured":"S. Andrews , FastQC: a quality control tool for high throughput sequence data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc. (2010)."},{"key":"2026080212250978000_2026.07.30.741768v1.56","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"2026080212250978000_2026.07.30.741768v1.57","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026080212250978000_2026.07.30.741768v1.58","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"2026080212250978000_2026.07.30.741768v1.59","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1138"},{"key":"2026080212250978000_2026.07.30.741768v1.60","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2026080212250978000_2026.07.30.741768v1.61","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1038\/nprot.2014.138","article-title":"The cellular thermal shift assay for evaluating drug target interactions in cells","volume":"9","year":"2014","journal-title":"Nature protocols"},{"key":"2026080212250978000_2026.07.30.741768v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3716"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.30.741768","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T19:25:20Z","timestamp":1785698720000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.30.741768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":62,"URL":"https:\/\/doi.org\/10.64898\/2026.07.30.741768","relation":{},"subject":[],"published":{"date-parts":[[2026,7,31]]},"subtype":"preprint"}}