Dual degradation of IKK1 and NR4A1 for AML therapy

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKKβ–NF-κB pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKKβ has been limited by serious toxicities, including neutrophilia. Here we identify IKKβ and NR4A1 as cooperative drivers of AML progression and develop a proteolysis-targeting chimera (PROTAC) to simultaneously degrade both proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits context-dependent oncogenic functions in AML. Notably, IKKβ and NR4A1 are highly expressed in AML associated with poor clinical outcomes and mutually enhance each other’s expression, playing synergistic roles to promote AML pathogenesis. To therapeutically target this pathway, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrol’s ability to bind both IKKβ and NR4A1. Among these compounds, the lead A9 induced potent cytotoxicity in multiple AML cell lines and primary AML samples through CRBN E3 ligase–dependent dual degradation of IKKβ and NR4A1. In vivo, A9 suppressed leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting dual PROTAC-mediated degradation as a promising therapeutic strategy.