Abstract
Acute myeloid leukemia (AML) is a common and aggressive blood cancer with the highest lethality rate among all leukemia subtypes. The cure rate of available therapeutic options is very low, underscoring an urgent need to develop novel and effective AML therapeutics. Here we identify IKKβ and NR4A1 as two closely related drivers of AML progression and develop a proteolysis targeting chimera (PROTAC) drug that has dual degradation activity against IKKβ and NR4A1. IKKβ and its downstream nuclear factor-κB (NF-κB) signaling are aberrantly activated in around 40% AML patients. However, nearly all IKKβ inhibitors have failed prior clinical trials due to their serious side effects such as neutrophilia and systematic inflammation. As opposed to the previously reported tumor suppressive role in AML, we found that NR4A1 promotes AML pathogenesis in a context-dependent manner. Here we designed, synthesized, and validated several celastrol-based PROTACs, with one lead compound A9 that effectively kills several AML cell lines and primary human AML cells via the degradation of IKKβ and NR4A1. At the mechanistic level, A9 degrades both targets through cereblon (CRBN) E3 ligase-mediated proteasomal system by forming ternary complexes with the target proteins and CRBN. More importantly, A9 attenuates AML disease progression in a clinically relevant KMT2A::MLLT3 mouse model and doesn't induce neutrophilia in vivo - a common side effect of IKKβ inhibitors. Our results reveal a potentially novel strategy to treat intractable and aggressive AMLs in the clinic. KEY POINTS: IKKβ and NR4A1 are clinically relevant mediators of AML pathogenesis.A novel celastrol-based PROTAC can effectively degrade both IKKβ and NR4A1 to disrupt AML pathogenesis.