Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β‐Thalassemia
β-thalassemia is a recessively inherited blood disorder affecting millions worldwide. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA methyltransferase (DNMT) inhibitors, although effective HbF inducers, currently are not approved for β-thalassemia treatment. Here, we report that DMT207, a novel non-nucleoside DNMT1 inhibitor, robustly reactivates HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. In a mouse model of β-thalassemia, DMT207 effectively elevates the levels of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly. Further multi-omics analyses expose γ-globin as one of the most sensitive genes with promoter demethylation and transcriptional activation following DMT207 treatment. Mechanistically, DMT207 traps DNMT1 into a catalytically inactive conformation and concurrently enhances its interaction with UHRF1, which partially contributes to DNMT1 degradation. These findings highlight the therapeutic potential of DMT207 for β-thalassemia and support its further preclinical development.
Authors
- Ruijie Gong (ORCID: https://orcid.org/0000-0002-6006-8547)
- Xianjiang Lan (ORCID: https://orcid.org/0000-0001-8208-2916)
- Yuhua Ye (ORCID: https://orcid.org/0000-0003-4443-3847)
- Cheng Luo (ORCID: https://orcid.org/0000-0003-3864-8382)
- Qinyu Liu (ORCID: https://orcid.org/0000-0001-9194-8320)
- Shibing Tang (ORCID: https://orcid.org/0000-0001-8592-3477)
- Quan Zhao (ORCID: https://orcid.org/0000-0002-8533-1938)
- Xiangqian Kong (ORCID: https://orcid.org/0009-0006-1670-8929)
- Shuyuan Ma
- Yijie Shen
- Peng Huang (ORCID: https://orcid.org/0009-0008-0043-2424)
- Feng Qin (ORCID: https://orcid.org/0000-0003-0209-9422)
- Shaopeng Liu (ORCID: https://orcid.org/0000-0003-0539-083X)
- Zhihai Li (ORCID: https://orcid.org/0000-0002-2816-6243)
- Qing Xiong (ORCID: https://orcid.org/0000-0002-8656-2041)
- Siyuan Xu (ORCID: https://orcid.org/0009-0006-4140-8557)
- Dongliang Wu
- Jiale Wei (ORCID: https://orcid.org/0009-0008-3274-4668)
- Chuxuan Peng
- Liangyi Zong
Institutions
- Shanghai Medical College of Fudan University (CN)
- China Pharmaceutical University (CN)
- Fudan University (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Shanghai Institute of Materia Medica (CN)
- Institute for Advanced Study (DE)
- Southern Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1002/advs.202513469
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Fudan University
- Guangzhou Municipal Science and Technology Bureau
- National Key Research and Development Program of China
- Shanghai Advanced Research Institute, Chinese Academy of Sciences
- Basic and Applied Basic Research Foundation of Guangdong Province