A novel 3-alkenylindol-2-one derivative selectively inhibits the growth of acute myeloid leukemia via modulation of the MYC-PRMT pathway.

The myelocytomatosis (MYC) oncogene is a central driver of acute myeloid leukemia (AML), but its direct targeting remains challenging due to its undruggable nature. Here, we identify 2-Methoxy-N-(2-oxo-3-(propan-2-ylidene)indolin-5-yl)benzenesulfonamide (3-alkenylindol-2-one) as a potent and selective inhibitor of AML cell proliferation through in vitro screening. In vivo studies demonstrated that 3-alkenylindol-2-one, when administered orally, markedly inhibited tumor growth in subcutaneous AML xenografts and lowered leukemic burden in systemic xenograft models, without inducing significant toxicity. Mechanistically, 3-alkenylindol-2-one exerts its anti-leukemic effects through dual mechanisms: (1) simultaneously downregulating MYC and multiple protein arginine methyltransferases (PRMTs), including PRMT1, PRMT4, PRMT5, and PRMT7, thereby reducing the accumulation of asymmetric and symmetric dimethylarginine (aDMA and sDMA) marks and preventing compensatory upregulation of methylarginine modifications caused by single-target PRMT inhibitors; and (2) upregulating CIITA and MHC II-related genes (CD74 and HLA-DQA), potentially enhancing antitumor immunity. By concurrently targeting MYC and multiple PRMTs, 3-alkenylindol-2-one overcomes the limitations of single-target therapies, offering a novel strategy to suppress proliferation and promote antitumor immunity in AML. These findings establish PRMTs as critical downstream mediators of MYC-driven leukemogenesis and position 3-alkenylindol-2-one as a promising clinical candidate for AML treatment, providing a mechanism-based approach to target MYC-driven leukemia through its downstream epigenetic regulators.