{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:33:39Z","timestamp":1768527219325,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,2]]},"group-title":"Cancer Biology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R35 GM134864"],"award-info":[{"award-number":["R35 GM134864"]}]},{"name":"National Science Foundation","award":["2040667"],"award-info":[{"award-number":["2040667"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Acute Myeloid Leukemia (AML) is a life-threatening hematologic malignancy. Despite recent therapeutic advances, rising incidence rates emphasize the urgent need for identification of new targets and therapies. Roles of interleukin receptor-associated kinases IRAK1\/4 are emerging in hematologic and solid malignancies. In AML, IRAK4 mRNA is overexpressed at diagnosis, relapses, in residual disease, and in FLT3-ITD-mutant cells, MDS, MPN, and MDS\/MPN-negative subtypes. Compared with hematopoietic stem cells, IRAK4 is elevated in t(15;17), inv(16)\/t(16;16), and t(11q23)\/MLL subtypes, correlating with poor survival. Here, we disclose anti-AML activity of PSP-0119, a novel IRAK4 PROTAC degrader. PSP-0119, inhibited IRAK4 kinase activity, NF-\u03ba\u03b2 activity, and IL-1\u03b2-induced IRAK4 phosphorylation. In-silico docking revealed interactions in CRBN\/IRAK4\/PSP-0119 ternary complex. PSP-0119 degraded IRAK4 in FLT3-mutant AML cell lines sparing FLT3-wild-type AML cells, FLT3-wild-type patient samples, and normal bone-marrow. Bulk-seq of PSP-0119 treated MOLM-13 cells revealed downregulation of eNOS, a poor AML prognosticator. PSP-0119 suppressed colony formation, cell viability, and MOLM-13 xenograft growth, and synergized with IRAK1 covalent inhibitor JH-X-119-01. PSP-0119 is metabolically stable, retaining 71% of parent compound at 60 minutes in human liver microsomes. In summary, IRAK4 degradation via PSP-0119 as a promising therapeutic strategy for treatment of FLT3-mutant AML.<\/jats:p>","DOI":"10.1101\/2025.09.30.679569","type":"posted-content","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T22:45:15Z","timestamp":1759445115000},"source":"Crossref","is-referenced-by-count":0,"title":["PSP-0119: Targeted IRAK4 Degradation as a Novel Therapeutic Strategy for FLT3-Mutant AML"],"prefix":"10.64898","author":[{"given":"Negar","family":"Khazan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cameron WA","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandhana","family":"Ravi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Lamere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niloy A.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj K.","family":"Khera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Liesveld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivasan","family":"Ekambaram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-4025","authenticated-orcid":false,"given":"Nikolay V.","family":"Dokholyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myla","family":"Strawderman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyu Kwang","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8726-4628","authenticated-orcid":false,"given":"Rachael","family":"Rowswell-Turner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael W.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard G.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1124-9202","authenticated-orcid":false,"given":"Rakesh K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025100618250919000_2025.09.30.679569v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1406184"},{"key":"2025100618250919000_2025.09.30.679569v1.2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.280802"},{"key":"2025100618250919000_2025.09.30.679569v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00425-3"},{"key":"2025100618250919000_2025.09.30.679569v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-020-00765-5"},{"key":"2025100618250919000_2025.09.30.679569v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-020-00376-1"},{"key":"2025100618250919000_2025.09.30.679569v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00509-w"},{"key":"2025100618250919000_2025.09.30.679569v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3346"},{"issue":"1","key":"2025100618250919000_2025.09.30.679569v1.8","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s40164-023-00422-1","article-title":"Role of innate immunological\/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review","volume":"12","year":"2023","journal-title":"Exp Hematol Oncol"},{"key":"2025100618250919000_2025.09.30.679569v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nri2691"},{"key":"2025100618250919000_2025.09.30.679569v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.041"},{"key":"2025100618250919000_2025.09.30.679569v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.3105cm1"},{"key":"2025100618250919000_2025.09.30.679569v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0314-5"},{"key":"2025100618250919000_2025.09.30.679569v1.13","doi-asserted-by":"crossref","unstructured":"Choudhary GS , Pellagatti A , Agianian B , Smith MA , Bhagat TD , Gordon-Mitchell S , et al. 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