title: YM753, a novel histone deacetylase inhibitor, exhibits antitumor activity with selective, sustained accumulation of acetylated histones in tumors in the WiDr xenograft model.
abstract: Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in vitro and in vivo. Various studies related to their antitumor activity and mechanism of action have been reported for HDAC inhibitors, but the relationship of their antitumor effects to their pharmacodynamic and pharmacokinetic properties in vivo has not ever fully characterized. We report here the discovery of a novel cyclic-peptide-based HDAC inhibitor, YM753. YM753 is a bacteria-derived natural product containing a disulfide bond. It potently inhibited HDAC enzyme with an IC50 of 2.0 nM in the presence of dithiothreitol. YM753 was rapidly converted to a reduced form in tumor cells, and then induced accumulation of acetylated histones, followed by p21WAF1/Cip1 expression, tumor cell growth inhibition and tumor-selective cell death. In an in vitro washout study, YM753 showed prolonged accumulation of acetylated histones in WiDr human colon carcinoma cells. In vivo YM753 dosing of mice harboring WiDr colon tumor xenografts significantly inhibited the tumor growth via sustained accumulation of acetylated histones in the tumor tissue. In a pharmacokinetic study, YM753 rapidly disappeared from the plasma, but its reduced form remained in the tumor tissue. Moreover, the accumulation of acetylated histones induced by YM753 was tumor tissue selective compared to several normal tissues. This study provides evidence that YM753 has antitumor activity that is the result of selective, sustained accumulation of acetylated histones in tumor tissues despite rapid disappearance of the drug from the plasma. These results suggest that the novel HDAC inhibitor, YM753 has attractive pharmacodynamic and pharmacokinetic properties giving it potential as an antitumor agent.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. nobuaki.shindoh@jp.astellas.com
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shindoh
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mori
authors.forename: Yoh
authors.initials: Y
authors.lastname: Terada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Oda
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Amino
authors.forename: Aya
authors.initials: A
authors.lastname: Kita
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Kin-Ya
authors.initials: KY
authors.lastname: Sohda
authors.forename: Koji
authors.initials: K
authors.lastname: Nagai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.forename: Yuhta
authors.initials: Y
authors.lastname: Masuoka
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Matsushime
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Furuichi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000378:metabolism; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays; D047630:Depsipeptides
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010456:Peptides, Cyclic; D011355:Prodrugs; C528968:RedYM compound; C528967:YM753 compound; D047630:Depsipeptides