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Ki11502, a Novel Multitargeted Receptor Tyrosine Kinase Inhibitor, Induces Growth Arrest and Apoptosis of Human Leukemia Cells in Vitro and in Vivo

Ki11502, a Novel Multitargeted 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, Akihito Yokoyama

Blood. 2008 May 15;111(10):5086-92.

PMID: 18309036

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP347155764-A	Ki11502		347155-76-4	Price

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