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  3. Complex-specific inhibitors for interrogating ATAC histone acetyltransferase complex

Complex-specific inhibitors for interrogating ATAC histone acetyltransferase complex

  • Nat Chem Biol. 2026 Mar;22(3):471-481. doi: 10.1038/s41589-025-02132-7.
Sha Liu # 1,  Jinzhao Liu # 2,  Yinqiao Wu # 1,  Xinyi Yao # 3,  Xiang Li 1,  Xinyu Dong 1,  Qi Li 1,  Hayden Jit Hei Cheung 1,  Kwan Yuen Wong 1,  Yuanyuan Li 3,  Mu He 4,  Chi-Leung Chiang 5,  Jason Wing Hon Wong 4,  Haitao Li 6 7 8,  Weiping Wang 9,  Xin Li 10,  Xiang David Li 11
Affiliations

Affiliations

  • 1 Department of Chemistry, The University of Hong Kong, Hong Kong, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology & Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
  • 3 State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  • 4 School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
  • 5 Department of Clinical Oncology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 6 State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Basic Medical Sciences, Tsinghua University, Beijing, China. lht@tsinghua.edu.cn.
  • 7 Tsinghua-Peking Center for Life Sciences, Beijing, China. lht@tsinghua.edu.cn.
  • 8 SXMU-TM Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China. lht@tsinghua.edu.cn.
  • 9 State Key Laboratory of Pharmaceutical Biotechnology & Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. wangwp@hku.hk.
  • 10 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China. lixin@szbl.ac.cn.
  • 11 Department of Chemistry, The University of Hong Kong, Hong Kong, China. xiangli@hku.hk.
  • # Contributed equally.
PMID: 41513852 DOI: 10.1038/s41589-025-02132-7
Abstract

Histone acetyltransferases (HATs) modify chromatin to regulate gene expression. Instead of acting alone, HATs function in complexes with Other proteins, leading to variations in substrate specificity, genomic localization and cellular function. To understand the complex-dependent roles of HATs, we present a chemical approach to specifically dissociate ATAC (Ada-two-A-containing) HAT complex from chromatin without perturbing Other complexes. Rather than targeting the shared HAT enzyme, we developed chemical inhibitors for an ATAC-specific subunit, YEATS2. The most effective inhibitor, LS-170, specifically reduced the chromatin occupancy of the ATAC complex, decreased the ATAC-dependent histone acetylation level and downregulated the expression of ATAC-governed genes, leading to significantly suppressed tumor growth in a lung Cancer mouse model. This study not only sheds light on the regulatory roles of the ATAC HAT complex in gene transcription but also provides evidence that the chemical inhibition of the ATAC complex can be a promising therapeutic strategy.

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