論文 - 詳細
| RRC ID | 10791 |
|---|---|
| 著者 | Mimasu S, Umezawa N, Sato S, Higuchi T, Umehara T, Yokoyama S. |
| タイトル | Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1 . |
| ジャーナル | Biochemistry |
| Abstract |
Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibition than tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a k(inact)/K(I) value of 4560 M(-1) s(-1). In comparison with tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations. |
| 巻・号 | 49(30) |
| ページ | 6494-503 |
| 公開日 | 2010-8-3 |
| DOI | 10.1021/bi100299r |
| PMID | 20568732 |
| MeSH | Antineoplastic Agents Cell Line Cyclopropanes / chemistry Cyclopropanes / pharmacology Drug Design Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology Histone Demethylases / antagonists & inhibitors* Humans Phenyl Ethers / chemistry Phenyl Ethers / pharmacology Structure-Activity Relationship Tranylcypromine / chemistry* Tranylcypromine / pharmacology* |
| IF | 2.865 |
| 引用数 | 123 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 94 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | 293T(RCB2202) |