|
|||||
|
|
Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations |
|
| Authors: | Nishiyama Uichi Yoshino Tetsuya Ozai Masako Yoshioka Rieko Fujisawa Motoko Ogasawara Yuko Kitahori Miyuki Yoshioka Eiji Kubo Kazuo Komeno Yukiko Kurokawa Mineo Ogawa Seishi Chiba Shigeru Osawa Tatsushi Kuwaki Tomoaki Hirai Hisamaru Miwa Atsushi |
| Affiliation: | aPharmaceutical Development Laboratories, Kirin Brewery Co. Ltd., Gunma, Japan bPharmaceutical Research Laboratories, Kirin Brewery Co. Ltd., Gunma, Japan cDepartment of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan dDepartment of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Tokyo, Japan eDepartment of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan |
| 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 (IC50) values of ≤5.9 and 43 nM, respectively. KRN383 also inhibited the proliferation of the ITD-positive cell lines with IC50 values of ≤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. |
| Keywords: | AML Flt3 ITD Tyrosine kinase inhibitor Quinoline KRN383 |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |