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Invest New Drugs (2011) 29:10941097 DOI 10.1007/s10637-010-9459-6
SHORT REPORT
Kit inhibitor APcK110 extends survival in an AML xenograft mouse model
Stefan Faderl & Carlos Bueso-Ramos & Zhiming Liu & Ashutosh Pal &
William Bornmann & Diana V. Ciurea & David Harris & Inbal Hazan-Halevy &
Hagop M. Kantarjian & Zeev Estrov
Received: 2 April 2010 /Accepted: 12 May 2010 /Published online: 3 June 2010 # Springer Science+Business Media, LLC 2010
Summary Background: Constitutive activation of kit contributes to pathogenesis of acute myeloid leukemia (AML) and targeting Kit may be of therapeutic benefit. APcK110, a novel inhibitor of Kit, has potent proapoptotic and antiproliferative activity in AML cell lines and primary AML samples. Here we extend our studies to the activity of APcK110 in a xenograft mouse model. Methods: After sub-lethal whole body radiation, OCI/AML3 cells were injected intravenously in NODSCID mice. Ten days later, either APcK110 or phosphate buffered saline (PBS) was injected intraperitoneally every other day. Kaplan-Meier estimates were used to calculate survival. Results: We show that 1) all mice injected with OCI/AML3 cells developed a clinical and histological picture consistent with myelomonocytic AML; and 2) survival of APcK110-treated mice was significantly longer compared with mice injected with PBS (p=.02). Conclusions: APcK110 is a novel kit kinase inhibitor with anti-AML activity in vitro and in vivo. Further evaluation in toxicology and clinical studies is warranted.
Keywords APcK110 . Acute myeloid leukemia . Kit inhibitor
Introduction
Acute myeloid leukemias (AML) are characterized by dysregulated hematopoiesis leading to expansion of hema-
topoietic progenitor cells in marrow, blood and other organs. This process is driven by acquisition of mutations inside hematopoietic progenitor cells that impair differentiation and stimulate proliferation thus providing a select group of cells a survival advantage over its undisturbed counterparts [5, 11, 17]. Although initiating events remain obscure and it can be assumed that several molecular hits are involved, a crucial role has been ascribed to abnormally activated protein tyrosine kinases [6].
This may not surprise as protein kinases function in key positions of almost all aspects of cell biology and therefore require tight control and regulation. Kit [stem cell factor (SCF) receptor] is a class III transmembrane receptor tyrosine kinase [9, 15]. Binding of its ligand SCF to kit results in receptor dimeriziation,...