Abstract Acute myeloid leukemia (AML) is a common aggressive blood cancer with a lethality rate among the highest of all leukemia subtypes. Cure rates of available therapeutic options are very low, underscoring an urgent need to develop more effective drugs. Here we identify IKKβ and NR4A1 as two closely related, clinically meaningful drivers of AML progression, and develop a proteolysis targeting chimera (PROTAC) drug that degrades both the proteins. IKKβ and the downstream NF-κB signaling are aberrantly activated in around 40% AML patients. However, IKKβ inhibitors exhibit serious side effects such as neutrophilia, limiting their therapeutic development. As opposed to the previously reported AML-suppressive role, we found that NR4A1 can also promote AML pathogenesis in different contexts. Moreover, IKKβ and NR4A1 were found to be highly expressed in AMLs associated with poor clinical outcomes, positively regulate each other’s expression, and synergize to maintain AML cell viability. We designed, synthesized, and validated an array of celastrol-based PROTACs as celastrol binds to both IKKβ and NR4A1, and identified one lead PROTAC, A9, that effectively kills several AML cell lines and primary human AML cells. Mechanistically, A9-induced AML cell killing was found to be dependent on CRBN E3 ligase-mediated dual degradation of IKKβ and NR4A1. In vivo, A9 attenuated AML disease progression in a clinically relevant KMT2A::MLLT3 mouse model and didn’t induce neutrophilia. Our results reveal a potentially novel strategy to treat intractable and aggressive AMLs in the clinic. Citation Format: Chandra Kumar Maharjan, Yi Liu, Yufeng Xiao, Bristy Podder, Tyler Montgomery, Lei Wang, Myung-Chul Kim, Zeng Jin, Seyedehalaleh Anvar, Alexandra Stevens, Ryan Kolb, Chen Zhao, Zhijian Qian, Jatinder K. Lamba, Guangrong Zheng, Weizhou Zhang. Dual targeting of IKKβ and NR4A1 for AML therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4511.
Maharjan et al. (Fri,) studied this question.