title: Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo.
abstract: Ki11502 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor with selectivity against platelet-derived growth factor receptor alpha/beta (PDGFRalpha/beta). Ki11502 (0.1-1 nM, 2 days) profoundly caused growth arrest, G(0)/G(1) cell-cycle arrest, and apoptosis associated with down-regulation of Bcl-2 family proteins in the eosinophilic leukemia EOL-1 cells having the activated FIP1-like 1/PDGFRalpha fusion gene. Ki11502 decreased levels of p-PDGFRalpha 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 PDGFRalphaT674I mutant. In addition, Ki11502 inhibited proliferation of biphenotipic leukemia MV4-11 and acute myelogenous leukemia MOLM13 and freshly isolated leukemia cells having activating mutations in FMS-like tyrosine kinase 3 (FLT3). This occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways, as measured by fluorescence-activated cell sorting using the phospho-specific antibodies. In addition, 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.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miwa
authors.forename: Taizo
authors.initials: T
authors.lastname: Tasaka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kuwayama
authors.forename: Kazuto
authors.initials: K
authors.lastname: Togitani
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C529896:Ki11502; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases