Potent Ikaros Degradation By the Cereblon E3 Ligase Modulator CC-92480 Is Effective in Combination with Menin-MLL1 Inhibition in MLL1-Rearranged and NPM1-Mutant AML

Acute myeloid leukemia (AML) has a poor prognosis despite intensive therapy. Novel therapies directed at molecular drivers of AML are needed. Ongoing clinical trials with inhibitors of the Menin and Mixed Lineage Leukemia 1 (KMT2A/MLL1) protein-protein interaction for patients with MLL1-rearranged (MLL1-r) and Nucleophosmin mutant (NPM1c) AML have promising early results. We have identified Ikaros degradation as a synergistic therapeutic target with Menin-MLL1 inhibition in MLL1-r AML and identified the novel cereblon E3 ligase modulator (CELMoD) CC-92480 as an efficacious compound in vitro and in vivo in MLL1-r and NPM1c AML models.