YTHDC1の小分子阻害剤による急性骨髄性白血病に対するマウスモデルでの戦略

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.