Kit inhibitor APcK110 extends survival in an AML xenograft mouse model.
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 NOD-SCID 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.
Faderl
Stefan
S
Department of Leukemia, Unit 428, MD Anderson Cancer Center, The University of Texas, 1515 Holcombe Blvd., Houston, TX 77030, USA. sfaderl@mdanderson.org
Bueso-Ramos
Carlos
C
Liu
Zhiming
Z
Pal
Ashutosh
A
Bornmann
William
W
Ciurea
Diana V
DV
Harris
David
D
Hazan-Halevy
Inbal
I
Kantarjian
Hagop M
HM
Estrov
Zeev
Z
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
C541943:(4-(7-(3,5-dimethyloxyphenyl)-1H-pyrazolo(3,4)pyridin-6-yl)-4-fluoro)benzene; D011720:Pyrazoles; D011725:Pyridines; D019009:Proto-Oncogene Proteins c-kit