2. Academic Validation
  3. Discovery of selenium-containing amino acid derivatives as novel ENL YEATS domain inhibitors via AlphaScreen-based high throughput screening

Discovery of selenium-containing amino acid derivatives as novel ENL YEATS domain inhibitors via AlphaScreen-based high throughput screening

  • Bioorg Chem. 2026 Sep 5:179:109989. doi: 10.1016/j.bioorg.2026.109989.
Siqi Guo 1,  Jianhao Li 2,  Yongxing Tao 3,  Xuecong Zhang 3,  Abdulla Yusuf 4,  Jia Jin 1,  Shijie Chen 5,  Ruihan Zhang 6,  Weilie Xiao 7,  Fei Ye 8
Affiliations

Affiliations

  • 1 College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
  • 4 College of Chemistry and Environmental Science, Laboratory of Xinjiang Native Medicinal and Edible Plant Resources Chemistry, Kashi University, China.
  • 5 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China.
  • 6 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address: [email protected].
  • 7 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address: [email protected].
  • 8 College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China. Electronic address: [email protected].
PMID: 42150408 DOI: 10.1016/j.bioorg.2026.109989
Abstract

Eleven-Nineteen-Leukemia Protein (ENL), a member of YEATS domain family, is a novel reader of lysine acetylation. Its deregulation is linked to various human diseases, especially Cancer. Therefore, ENL has garnered significant interest as a potential therapeutic target. Herein, we report the discovery of novel ENL YEATS domain inhibitors via high-throughput screening. Hit compounds DC_E35 and DC_E36 were identified and structurally optimized, yielding the potent derivative DC_E35_5d (IC50 = 62.0 ± 14.7 nM). Biophysical assays confirmed direct target engagement. In MOLM-13 cells, DC_E35_5d reduced ENL thermal stability, downregulated the oncogene MYC, and synergized with the Bromodomain inhibitor JQ-1 to suppress cell growth. Hence, DC_E35_5d represents a novel class of ENL YEATS domain inhibitors with novel scaffold and has broad prospects for being a probe for ENL-related academic and clinical research.

Keywords

Acute myeloid leukemia; ENL inhibitor; Epigenetics; Histone lysine acetylation; YEATS domain.

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