WP1066 is a novel analogue of the JAK2 inhibitor AG490. WP1066 inhibited OCIM2 cell multiplication by inducing accumulation of cells at the G(0)-G(1) phase of the cell cycle. WP1066 concentrations in the low micromolar range induced time- and dose-dependent antiproliferative and proapoptotic effects in HEL cells. In Caki-1 and 786-O renal cancer cells, 5 muM WP1066 prevented the phosphorylation of STAT3, and 2.5 muM WP1066 significantly (P<0.01) inhibited cell survival and proliferation. WP1066 suppressed the expression of Bcl-2, induced apoptosis, and inhibited the basal and hypoxia-induced expression of HIF1alpha and HIF2alpha, as well as vascular endothelial growth factor secretion into cell culture medium. Inhibition of p-STAT3 by WP1066 was enhanced with CTX in a dose-dependent manner. WP1066 is active both in vitro and ex vivo.
|Cell lines||Caki-1 and 786-O cells line|
|Preparation method||Cell viability was assessed by the MTS assay using the Cell Titer96 AQueous Non-Radioactive Cell Proliferation Assay (Promega, Madison, WI, USA) according to the manufacturer's instructions. Briefly, cells were incubated overnight in 96-well plates (3 × 103 cells/well) and then treated for 48 h with the indicated concentration of WP1066 (in DMSO) or with the corresponding amount of DMSO. Two hours after adding MTS, plates were read in a microplate autoreader at a wavelength of 490 nm. The results were expressed as the mean optical density of the six-well set for each group, and the plates were measured twice with similar results. For cell counts, after being incubated overnight in six-well plates (2 × 104 cells/well in triplicate), cells were treated with 2.5 or 5 μm WP1066 or with the corresponding amount of DMSO. Total cell numbers in three independent wells in each group were counted at the indicated time by using a hemocytometer, and the mean value of four fields was recorded.|
|Concentrations||0, 2.5 and 5 μM|
|Incubation time||24 and 48 h|
|Animal models||nude mice bearing Caki-1 cells xenograft model|
|Formulation||mixture of 20 parts DMSO to 80 parts polyethylene glycol 300|
|Dosages||40mg/kg once per day (5 days on and 2 days off) for 18 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 70 mg/mL|
The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models.
Hatiboglu MA, et al. Int J Cancer. 2012 Jul 1;131(1):8-17. PMID: 21792892.
STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma.
Horiguchi A, et al. Br J Cancer. 2010 May 25;102(11):1592-9. PMID: 20461084.
WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation.
Verstovsek S, et al. Clin Cancer Res. 2008 Feb 1;14(3):788-96. PMID: 18245540.
WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells.
Ferrajoli A, et al. Cancer Res. 2007 Dec 1;67(23):11291-9. PMID: 18056455.
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