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
リソース情報
ヒト・動物細胞 293T(RCB2202)