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Related Experiment Video

Updated: Sep 11, 2025

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
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Identification of a Selective YTHDF1 Inhibitor Targeting the m6A Recognition Domain for Breast Cancer.

Yongya Wu1, Guotai Feng1, Wen Shuai1

  • 1State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Children's Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, No. 17, Section 3, Renmin South Road, Chengdu, 610041, China.

Angewandte Chemie (International Ed. in English)
|August 19, 2025
PubMed
Summary

Researchers developed SKLB-Y13, the first selective inhibitor targeting YTHDF1, a protein linked to breast cancer. This small molecule disrupts cancer cell growth and promotes apoptosis by inhibiting YTHDF1

Keywords:
AntiproliferationBreast cancerDrug discoverySelective inhibitorYTHDF1

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • YTH domain-containing family protein 1 (YTHDF1) is a key N6-methyladenosine (m6A) reader involved in protein synthesis.
  • Abnormal YTHDF1 expression is linked to breast cancer (BC) progression.
  • Existing YTHDF1 inhibitors lack selectivity and potency due to YTH domain homology.

Purpose of the Study:

  • To develop the first small-molecule inhibitor with exclusive targeting of YTHDF1.
  • To investigate the therapeutic potential of selective YTHDF1 inhibition in breast cancer.

Main Methods:

  • Structural optimization of a 4,5,6,7-tetrahydrothieno[2,3-c]pyridine scaffold to create SKLB-Y13.
  • Site-directed mutagenesis to confirm interactions with YTHDF1-specific residues (Tyr397 and Trp470).
  • Cellular and in vivo studies, chemical proteomics, and pharmacokinetic analysis.

Main Results:

  • SKLB-Y13 selectively targets the YTHDF1 m6A-binding pocket with an IC50 of 0.76 µM.
  • SKLB-Y13 demonstrates superior selectivity for YTHDF1 over other YTH family proteins.
  • SKLB-Y13 disrupts YTHDF1-PRPF6 mRNA interaction, inhibits BC proliferation, and promotes apoptosis.

Conclusions:

  • SKLB-Y13 is the first selective YTHDF1 inhibitor, offering a novel chemical probe for m6A-dependent oncogenesis research.
  • This inhibitor shows promise as a starting point for precision therapies against YTHDF1-overexpressing breast cancer.