Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations.
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.
Nishiyama
Uichi
U
Pharmaceutical Development Laboratories, Kirin Brewery Co. Ltd., Gunma, Japan.
Yoshino
Tetsuya
T
Ozai
Masako
M
Yoshioka
Rieko
R
Fujisawa
Motoko
M
Ogasawara
Yuko
Y
Kitahori
Miyuki
M
Yoshioka
Eiji
E
Kubo
Kazuo
K
Komeno
Yukiko
Y
Kurokawa
Mineo
M
Ogawa
Seishi
S
Chiba
Shigeru
S
Osawa
Tatsushi
T
Kuwaki
Tomoaki
T
Hirai
Hisamaru
H
Miwa
Atsushi
A
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
D000964:Antimetabolites, Antineoplastic; C523070:KRN383; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D014508:Urea; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3