Submitted June 27, 2007
Accepted February 14, 2008
Ki11502, a novel multi-targeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo
Chie Nishioka, Takayuki Ikezoe*, Jing Yang, Atsushi Miwa, Taizo Tasaka, Yoshio Kuwayama, Kazuto Togitani, H Phillip Koeffler, and Akihito Yokoyama
Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan
Discovery Research Laboratories, Kirin Pharma Co., Ltd., Gumma, Japan
Division of Hematology, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan
Department of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States
* Corresponding author; email: ikezoet{at}kochi-u.ac.jp.
Ki11502 is a novel multi-targeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet derived growth factor receptor alpha/beta (PDGFR
/
). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G0/G1 cell cycle arrest, and apoptosis associated with downregulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFR fusion gene. Ki11502 decreased levels of p-PDGFR and its downstream signals including p-Akt, p-ERK, and p-STAT5 in EOL-1 cells. Of note, Ki11502 was also active against imatinib-resistant PDGFRT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogeneous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in paralleled with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. Also, Ki11502 totally inhibited proliferation of EOL-1 cells growing as tumor xenografts in SCID mice without any noticeable adverse effects. Taken together, Ki11502 has profound antiproliferative effects on select subsets of leukemia including those possessing imatinib-resistant mutation.
