論文 - 詳細
| RRC ID | 86544 |
|---|---|
| 著者 | Yang Z, Sun W, Huang Q, Li Y, Yuan M, Yang Y, Zhao H, Liu Z, Zeng X, Wang F, Jiang Y, Zhao Y, Chen R. |
| タイトル | Deep learning-assisted discovery of a potent and cell-active inhibitor of RNA N6-methyladenosine recognition protein YTHDC2. |
| ジャーナル | Nat Commun |
| Abstract |
YTHDC2, a unique YTH-domain-containing protein that recognizes N6-methyladenosine (m6A) on RNA, plays critical roles in diverse pathological processes and represents a promising therapeutic target. Despite its potential, no potent small-molecule inhibitors have been reported to date. To bridge this gap, we develop EPMolGen, a deep learning-based molecular generative model that explicitly incorporates the electrostatic features of receptor proteins. The model achieves state-of-the-art performance in dry-lab validations. Using EPMolGen, we identify H3, a YTHDC2 inhibitor with an IC50 of 16.84 μM. Subsequent structural optimization of H3 yields DC2-C1, a highly potent compound with an IC50 of 0.168 μM against YTHDC2 and selectivity over other YTH-domain proteins. In cellular assays, DC2-C1 effectively targets YTHDC2. Notably, DC2-C1 treatment substantially reduces the expression levels of multiple target mRNAs of YTHDC2, leading to phenotypic suppression of related cells. Overall, this study highlights the great potential of deep learning in drug discovery and provides a promising lead compound for drug development targeting YTHDC2. |
| 巻・号 | 17(1) |
| ページ | 46 |
| 公開日 | 2026-1-6 |
| DOI | 10.1038/s41467-025-65542-0 |
| PII | 10.1038/s41467-025-65542-0 |
| PMID | 41495018 |
| PMC | PMC12775497 |
| MeSH | Adenosine* / analogs & derivatives Adenosine* / chemistry Adenosine* / metabolism Deep Learning* Drug Discovery* / methods Humans RNA / metabolism RNA Helicases RNA, Messenger / genetics RNA, Messenger / metabolism RNA-Binding Proteins* / antagonists & inhibitors RNA-Binding Proteins* / chemistry RNA-Binding Proteins* / genetics RNA-Binding Proteins* / metabolism |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Bluesky |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MH7A(RCB1512) |