Reference - Detail
| RRC ID | 10791 |
|---|---|
| Author | Mimasu S, Umezawa N, Sato S, Higuchi T, Umehara T, Yokoyama S. |
| Title | Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1 . |
| Journal | 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. |
| Volume | 49(30) |
| Pages | 6494-503 |
| Published | 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 |
| Times Cited | 123 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 94 |
| Altmetric score changes over past 6months | 3.0 |
| Resource | |
| Human and Animal Cells | 293T(RCB2202) |