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: Chie Nishioka, Takayuki Ikezoe, Jing Yang, Atsushi Miwa, Taizo Tasaka, Yoshio Kuwayama, Kazuto Togitani, H Phillip Koeffler, Akihito Yokoyama
• Journal: Blood (Blood) Vol. 111 Issue 10 Pg. 5086-92 (May 15 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18309036 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ki11502
• Protein Kinase Inhibitors
• Quinolines
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Leukemia (drug therapy, pathology)
• Mice
• Mice, SCID
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinolines (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Transplantation, Heterologous
• Treatment Outcome