title: Discovery and characterization of NK13650s, naturally occurring p300-selective histone acetyltransferase inhibitors.
abstract: The histone acetyltransferase (HAT) activity of p300 is essential for androgen receptor (AR) function. Androgen-independent prostate cancer cells require AR-mediated transcriptional activation for their growth. These observations indicate that p300 HAT is a promising target to overcome such hormone-resistant cancer cells. We sought p300 HAT inhibitors among microbial metabolites. By culturing a production strain belonging to Penicillium, we identified two new compounds, NK13650A and NK13650B, which were obtained as specific p300 HAT inhibitors. Structural analyses of these compounds elucidated that NK13650s have novel chemical structures comprising several amino acids and citrate. We applied a newly developed biosynthesis-based method to reveal the absolute configuration at the citrate quaternary carbon. This was accomplished by feeding a (13)C-labeled biosynthetic precursor of citrate. NK13650s selectively inhibited the activity of p300 HAT but not that of Tip60 HAT. NK13650s showed inhibitory activity against agonist-induced AR transcriptional activation, and NK13650A treatment inhibited hormone-dependent and -independent growth of prostate cancer cells.
authors.affiliation: Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan. tohyamas@bikaken.or.jp
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Tohyama
authors.forename: Arihiro
authors.initials: A
authors.lastname: Tomura
authors.forename: Noriko
authors.initials: N
authors.lastname: Ikeda
authors.forename: Masaki
authors.initials: M
authors.lastname: Hatano
authors.forename: Junko
authors.initials: J
authors.lastname: Odanaka
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kubota
authors.forename: Maya
authors.initials: M
authors.lastname: Umekita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sawa
authors.forename: Tomio
authors.initials: T
authors.lastname: Morino
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002951:Citrates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D054659:Diketopiperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D010407:Penicillium / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002951:Citrates; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; C579028:NK13650A; C579029:NK13650B; D051548:Histone Acetyltransferases