Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models

Dysregulation of RNA N⁶-methyladenosine (m⁶A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m⁶A reader. We provided a high-resolution cocrystal structure of the YTHDC1-YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m⁶A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m⁶A readers is a potential strategy in the treatment of hematologic cancers.