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: Uichi Nishiyama, Tetsuya Yoshino, Masako Ozai, Rieko Yoshioka, Motoko Fujisawa, Yuko Ogasawara, Miyuki Kitahori, Eiji Yoshioka, Kazuo Kubo, Yukiko Komeno, Mineo Kurokawa, Seishi Ogawa, Shigeru Chiba, Tatsushi Osawa, Tomoaki Kuwaki, Hisamaru Hirai, Atsushi Miwa
• Journal: Leukemia research (Leuk Res) Vol. 30 Issue 12 Pg. 1541-6 (Dec 2006) ISSN: 0145-2126 [Print] England
• PMID: 16603240 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• KRN383
• Protein Kinase Inhibitors
• Quinolines
• Urea
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Administration, Oral
• Animals
• Antimetabolites, Antineoplastic (administration & dosage, chemistry)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, SCID
• Molecular Structure
• Phosphorylation
• Point Mutation
• Protein Kinase Inhibitors (administration & dosage, chemistry)
• Quinolines (pharmacology)
• Survival Rate
• Time Factors
• Urea (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, genetics, metabolism)