{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:58:53Z","timestamp":1785405533059,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,27]]},"group-title":"Cancer Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["CA260239"],"award-info":[{"award-number":["CA260239"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CA290792"],"award-info":[{"award-number":["CA290792"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CA269661"],"award-info":[{"award-number":["CA269661"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"name":"UF Health Cancer Center","award":["P30CA247796"],"award-info":[{"award-number":["P30CA247796"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKK\u03b2\u2013NF-\u03baB pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKK\u03b2 has been limited by serious toxicities, including neutrophilia. Here we identify IKK\u03b2 and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKK\u03b2 and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKK\u03b2 and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrol\u2019s ability to bind both IKK\u03b2 and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase\u2013dependent degradation of IKK\u03b2 and\/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKK\u03b2 and NR4A1 as a promising therapeutic strategy.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Plain language summary<\/jats:title>\n                  <jats:p>Acute myeloid leukemia (AML) is a predominant form of blood cancer with devastating consequences in both young and adult populations. Despite some advances in AML treatment over the last decade, there is still an unmet medical need to develop new drugs for difficult-to- treat AMLs. We discover that two proteins, namely IKK\u03b2 and NR4A1, play important roles in promoting the AML disease and could be associated with more severe AML subtypes. To target and destroy those proteins within AML cells, we employ a novel targeted protein degradation approach, which involved design, synthesis, and screening of PROTAC drugs, to discover a drug possessing pronounced AML cell killing activity by virtue of IKK\u03b2 and NR4A1 degradations. The drug also significantly reduces AML progression in mice without any noticeable adverse effects. Our current efforts involve more comprehensively testing the benefit of the drug (and its analogs) in a wide range of clinically relevant AML models.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>IKK\u03b2 and NR4A1 are clinically relevant drivers of AML pathogenesis.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>A novel celastrol-based PROTAC can effectively degrade IKK\u03b2 and\/or NR4A1 to potentially treat AML.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                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