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PreprintCC BYChemRxiv

A Pan-YTHDF Probe Enables Chemical Modulation and Dissection of RNA m6A Reader Programs

  • Wenlong Li1,2,3
  • Linda Zhang1,2,3
  • Zhong Zheng1,2,3
  • Pingluan Wang1,2,3
  • Yutao Zhao1,2,3
  • Yanming Chen1,2,3
  • Hui-lung Sun1,2,3
  • Fei Ji1,2,3
  • Peng Xia1,2,3
  • Xinyuan Ma1,2,3
  • Xinjian Mao4
  • Bixia Zhang5,2
5 more authors
  • Yusuf Noffel1,2,3,6
  • Linheng Li4
  • Minglei Zhao5,2
  • Liangliang Wang7,8
  • Chuan He1,2,3
8 affiliations
  1. 1Institute for Biophysical Dynamics
  2. 2University of Chicago
  3. 3Howard Hughes Medical Institute
  4. 4Stowers Institute for Medical Research
  5. 5Department of Biochemistry and Molecular Biology
  6. 6Medical Scientist Training Program
  7. 7Institute of Microbiology
  8. 8Chinese Academy of Sciences
Open at sourcePDFDOICite

Abstract

Genetic perturbation has been central to defining the functions of RNA modification binding proteins (readers), but knockout approaches remove the entire protein and cannot readily distinguish modification-dependent reader activity from other protein-associated functions. Small molecules provide an orthogonal strategy by directly perturbing the reader protein–RNA recognition event while preserving the reader protein. Here we report DF142, a cell-active pan-YTHDF chemical probe developed through an m6A-anchored design strategy. Structure-guided optimization yielded a high-affinity ligand that engages endogenous YTHDF proteins, blocks YTHDF–m6A RNA recognition, and displays a favorable selectivity profile. In mouse B cells, DF142 closely recapitulated the transcriptional effects of genetic Ythdf1/2 loss but induced minimal effects in Ythdf1/2-deficient cells at the applied dose range, distinguishing m6A-dependent from putative m6A-independent programs. In AML cells, application of DF142 revealed a leukemia-relevant RNA program associated with YTHDF–m6A interactions. Its activity in cancer cells and mouse models further demonstrates the utility of DF142 for interrogating YTHDF function in disease-relevant settings. Together, these findings establish DF142 as a chemical probe for dissecting m6A-dependent YTHDF biology.

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Cite

BibTeXRIS
BibTeX
@misc{li2026panythdf,
  title = {{A Pan-YTHDF Probe Enables Chemical Modulation and Dissection of RNA m6A Reader Programs}},
  author = {Wenlong Li and Linda Zhang and Zhong Zheng and Pingluan Wang and Yutao Zhao and Yanming Chen and Hui-lung Sun and Fei Ji and Peng Xia and Xinyuan Ma and Xinjian Mao and Bixia Zhang and Yusuf Noffel and Linheng Li and Minglei Zhao and Liangliang Wang and Chuan He},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009365/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009365/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - A Pan-YTHDF Probe Enables Chemical Modulation and Dissection of RNA m6A Reader Programs
AU  - Wenlong Li
AU  - Linda Zhang
AU  - Zhong Zheng
AU  - Pingluan Wang
AU  - Yutao Zhao
AU  - Yanming Chen
AU  - Hui-lung Sun
AU  - Fei Ji
AU  - Peng Xia
AU  - Xinyuan Ma
AU  - Xinjian Mao
AU  - Bixia Zhang
AU  - Yusuf Noffel
AU  - Linheng Li
AU  - Minglei Zhao
AU  - Liangliang Wang
AU  - Chuan He
PY  - 2026
DA  - 2026/09/23
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009365/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009365/v1
AB  - Genetic perturbation has been central to defining the functions of RNA modification binding proteins (readers), but knockout approaches remove the entire protein and cannot readily distinguish modification-dependent reader activity from other protein-associated functions. Small molecules provide an orthogonal strategy by directly perturbing the reader protein–RNA recognition event while preserving the reader protein. Here we report DF142, a cell-active pan-YTHDF chemical probe developed through an m6A-anchored design strategy. Structure-guided optimization yielded a high-affinity ligand that engages endogenous YTHDF proteins, blocks YTHDF–m6A RNA recognition, and displays a favorable selectivity profile. In mouse B cells, DF142 closely recapitulated the transcriptional effects of genetic Ythdf1/2 loss but induced minimal effects in Ythdf1/2-deficient cells at the applied dose range, distinguishing m6A-dependent from putative m6A-independent programs. In AML cells, application of DF142 revealed a leukemia-relevant RNA program associated with YTHDF–m6A interactions. Its activity in cancer cells and mouse models further demonstrates the utility of DF142 for interrogating YTHDF function in disease-relevant settings. Together, these findings establish DF142 as a chemical probe for dissecting m6A-dependent YTHDF biology.
ER  -