9MB3

Crystal structure of YTHDC1 in complex with YL-5092

Summary for 9MB3

• Entry DOI: 10.2210/pdb9mb3/pdb
• Descriptor: YTH domain-containing protein 1, N-[4-(1,3-thiazol-5-yl)phenyl]-4-[2-(trifluoromethyl)phenyl]carbonyl-1H-pyrrole-2-carboxamide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: rna-binding proteins, rna, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 39141.00

Authors

Zhang, H.,Yang, S. (deposition date: 2025-03-15, release date: 2025-12-24, Last modification date: 2026-04-15)

Primary citation

Zhang, H.,Li, Y.,Zhao, Y.,Wang, F.,Lin, G.,Niu, T.,Li, H.,Li, Y.,Liu, L.,Liang, Y.,Shen, Y.,Yi, Y.,Zhou, H.,Lou, S.,Ye, Y.,He, Y.,Yang, R.,Yao, R.,Tian, C.,Zhou, P.,Wu, M.,Chen, M.,Xu, H.,You, J.,Liao, Y.,Yang, C.,Zhao, A.,Chen, C.,Li, L.,Pei, S.,Yang, S.
Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models.
Sci Transl Med, 18:eadu3137-eadu3137, 2026

PubMed Abstract: Dysregulation of RNA N-methyladenosine (mA) 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 mA 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 mA 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 mA readers is a potential strategy in the treatment of hematologic cancers.

PubMed: 41637525
DOI: 10.1126/scitranslmed.adu3137

Experimental method

X-RAY DIFFRACTION (1.6 Å)