title: Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations.
abstract: Activating mutations of Fms-like tyrosine kinase 3 (Flt3) are the most common genetic abnormalities found in acute myeloid leukemia (AML) and represent potential therapeutic targets. The novel Flt3 inhibitor KRN383 inhibited the autophosphorylation of Flt3 bearing internal tandem duplications (ITDs) and the Asp835Tyr (D835Y) point mutation with half-maximal inhibitory concentration (IC(50)) values of < or =5.9 and 43 nM, respectively. KRN383 also inhibited the proliferation of the ITD-positive cell lines with IC(50) values of < or =2.9 nM. A single oral administration of 80 mg/kg of KRN383 eradicated ITD-positive xenograft tumors in nude mice and prolonged the survival of SCID mice carrying ITD-positive AML cells. The effectiveness of a single oral dose of KRN383 suggests that it has the potential to be used in a wide variety of clinical regimens, including multicycle and combination therapies.
authors.affiliation: Pharmaceutical Development Laboratories, Kirin Brewery Co. Ltd., Gunma, Japan.
authors.forename: Uichi
authors.initials: U
authors.lastname: Nishiyama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoshino
authors.forename: Masako
authors.initials: M
authors.lastname: Ozai
authors.forename: Rieko
authors.initials: R
authors.lastname: Yoshioka
authors.forename: Motoko
authors.initials: M
authors.lastname: Fujisawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ogasawara
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kitahori
authors.forename: Eiji
authors.initials: E
authors.lastname: Yoshioka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kubo
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komeno
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Osawa
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Hisamaru
authors.initials: H
authors.lastname: Hirai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miwa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D010766:Phosphorylation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D011804:Quinolines / Q000494:pharmacology*; D015996:Survival Rate; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C523070:KRN383; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D014508:Urea; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3