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Currently, there is no effective treatment for PDAC patients. The development of novel agents to effectively treat these cancers remains an unmet clinical need. FL118, a novel anticancer small molecule, exhibits high efficacy against cancers; however, the direct biochemical target of FL118 is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>FL118 affinity purification, mass spectrometry, Nanosep centrifugal device and isothermal titration calorimetry were used for identifying and confirming FL118 binding to DDX5\/p68 and its binding affinity. Immunoprecipitation (IP), western blots, real\u2010time reverse transcription PCR, gene silencing, overexpression (OE) and knockout (KO) were used for analysing gene\/protein function and expression. Chromatin IP was used for analysing protein\u2010DNA interactions. The 3\u2010[4,5\u2010dimethylthiazol\u20102\u2010yl]\u20102,5\u2010diphenyltetrazolium bromid assay and human PDAC\/CRC cell\/tumour models were used for determining PDAC\/CRC cell\/tumour in vitro and in vivo growth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We discovered that FL118 strongly binds to, dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway without decreasing DDX5 mRNA. Silencing and OE of DDX5 indicated that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins, including survivin, Mcl\u20101, XIAP, cIAP2, c\u2010Myc and mutant Kras. Genetic manipulation of DDX5 in PDAC cells affects tumour growth. PDAC cells with DDX5 KO are resistant to FL118 treatment. Our human tumour animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and CRC tumours that have a high expression of DDX5, while FL118 exhibits less effectiveness in PDAC and CRC tumours with low DDX5 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a \u2018molecular glue degrader\u2019 to directly glue DDX5 and ubiquitination regulators together to degrade DDX5.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.881","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T12:00:41Z","timestamp":1653307241000},"source":"Crossref","is-referenced-by-count":39,"title":["FL118, acting as a \u2018molecular glue degrader\u2019, binds to, dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c\u2010Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiang","family":"Ling","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics Roswell Park Comprehensive Cancer Center  Buffalo New York USA"},{"name":"Canget BioTekpharma LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics Roswell Park Comprehensive Cancer Center  Buffalo New York USA"},{"name":"Canget BioTekpharma LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ieman A. M.","family":"Aljahdali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics Roswell Park Comprehensive Cancer Center  Buffalo New York USA"},{"name":"Department of Cellular &amp; Molecular Biology Roswell Park Comprehensive Cancer Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqun","family":"Liao","sequence":"additional","affiliation":[{"name":"Canget BioTekpharma LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreevidya","family":"Santha","sequence":"additional","affiliation":[{"name":"Canget BioTekpharma LLC  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Fountzilas","sequence":"additional","affiliation":[{"name":"Department of Medicine Roswell Park Comprehensive Cancer Center  Buffalo New York USA"},{"name":"Developmental Therapeutics (DT) Program Roswell Park Comprehensive Cancer Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Boland","sequence":"additional","affiliation":[{"name":"Department of Medicine Roswell Park Comprehensive Cancer Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2299-7951","authenticated-orcid":false,"given":"Fengzhi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Therapeutics Roswell Park Comprehensive Cancer Center  Buffalo New York USA"},{"name":"Developmental Therapeutics (DT) Program Roswell Park Comprehensive Cancer Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201014\u20100155"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21654"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/25141"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/70242"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/0264-6021:3440305"},{"issue":"13","key":"e_1_2_7_7_1","first-page":"3143","article-title":"The cancer antiapoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle\u2010dependent expression","volume":"59","author":"Li F","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.10.6707"},{"key":"e_1_2_7_9_1","unstructured":"LiF inventor; Health Research Inc. 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