| 项目编号 | PRJCA049126 | ||||||||||
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| 项目标题 | DMI46 reprograms the DNA methylome and transcriptome to exert anti-leukemic effects | ||||||||||
| 涉及领域 | Medical | ||||||||||
| 数据类型 |
Epigenomics
Transcriptome or Gene expression Raw sequence reads |
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| 物种名称 | Homo sapiens | ||||||||||
| 描述信息 | Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Non-nucleoside, DNMT1-selective inhibitors offer a promising alternative. To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7-azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust anti-leukemic effects and favorable tolerability. Cryo-electron microscopy (cryo-EM) studies reveal that the 7-azaindole inhibitor exhibits enhanced intercalation into hemi-methylated CpG dyads and increased minor-groove contacts within the DNMT1/hemi-methylated DNA complex compared to GSK5032. These structural features enable sustained DNMT1 targeting and significant anti-proliferative activity of DMI46 in GSK5032-resistant acute myeloid leukemia (AML) cells. We also demonstrate DMI46's capacity to overcome AML resistance to nucleoside-based HMAs both in vitro and in vivo. These findings introduce a distinct DNMT1i chemotype with enhanced on-target engagement and broad applicability against HMA-resistant AML. | ||||||||||
| 样品范围 | Monoisolate | ||||||||||
| 发布日期 | 2025-11-22 | ||||||||||
| 出版信息 |
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| 提交者 | xiangqian kong (kong_xiangqian@gibh.ac.cn) | ||||||||||
| 提交单位 | GUANGZHOU INSTITUTES OF BIOMEDICINE AND HEALTH,CHINESE ACADEMY OF SCIENCES | ||||||||||
| 提交日期 | 2025-10-24 |
| 资源名称 | 描述 |
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| BioSample (12) show | - |