Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models
Menée à l'aide de modèles murins de leucémie myéloïde aiguë, cette étude met en évidence l'intérêt de YL-5092, un inhibiteur de la protéine nucléaire YTHDC1, pour supprimer la maladie et altérer le fonctionnement des cellules souches cancéreuses en préservant les cellules souches hématopoïétiques saines
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.
Science Translational Medicine , résumé, 2026