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The small molecule drug CX-5461 exhibits dual target specificity, acting as a first-in-class ribosome biogenesis inhibitor to induce the nucleolar surveillance pathway (NSP), as well as to poison Topoisomerase II\u03b1 (TOPIIA) to induce DNA damage. We conducted a phenotypic screen of FDA-approved drugs to identify compounds that synergies with CX-5461 to enhance the therapeutic efficacy of this drug in incurable AML. The pan-CDK inhibitors Dinaciclib and Flavopiridol were identified as efficient combinatorial therapies with CX-5461. Dinaciclib acts synergistically across a genetically divergent panel of human AML cell lines, significantly improves survival in murine AML models, and reduces colony formation in primary human AML samples. Synergy was attributable, at least partially, to combinatorial activation of the NSP. Both agents independently stabilized p53 but produced distinct biological outcome; Dinaciclib driving rapid apoptosis and CX-5461 primarily promoting cell-cycle arrest; which together yielded efficient tumor clearance and delayed onset of therapy resistance. 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The novel RNA polymerase I transcription inhibitor PMR-116 exploits a critical therapeutic vulnerability in a broad-spectrum of high MYC malignancies. bioRxiv, 2025. https:\/\/www.biorxiv.org\/content\/10.1101\/2025.04.19.649466v1.","DOI":"10.1101\/2025.04.19.649466"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-03148-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-03148-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-03148-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:02:47Z","timestamp":1791486167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-03148-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":43,"alternative-id":["3148"],"URL":"https:\/\/doi.org\/10.1038\/s41375-026-03148-1","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"8 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All methods described in the study were performed in accordance with relevant institutional guidelines and regulations. Animal experimentation was conducted under animal ethics protocols approved by the Australian National University Animal Ethics Committee (A2015\/12 & A2018\/48) and the Peter MacCallum Cancer Centre Animal Ethics Committee (E462). All experimental work was conducted in compliance with the Australian Code for the Care and Use of Animals for Scientific Purposes. Experimentation using primary AML cells was performed under protocols approved by the Central Adelaide Local Health Network human research ethics (HREC\/18\/CALHN\/588). Informed consent was obtained from all participants.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}