GSK1838705A is a potent inhibitor of IGF-IR, IR and ALK with IC50 of 2.0 nM, 1.6 nM and 0.5 nM, respectively. The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase first identified as the product of a gene rearrangement in Anaplastic Large Cell Lymphoma. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers. GSK1838705A (60 mg/kg) inhibits the growth of established Karpas-299 xenografts with 93% tumor growth inhibition, with no effect on weights of the rats.
|Cell lines||L-82, SUP-M2, SK-ES and MCF-7 cells|
|Preparation method||Cell Proliferation Assays
Cells were seeded in 96-well dishes, incubated overnight at 37°C, and treated with DMSO or GSK1838705A for 72 h. For the NIH-3T3/LISN proliferation assays, cells were seeded on collagen-coated 96-well tissue culture plates (BD Biosciences) and allowed to adhere for 24 h. The medium was replaced with serum-free medium and the cells were treated with GSK1838705A for 2 h. Cells were incubated for 72 h after addition of IGF-I (30 ng/mL). Cell proliferation was quantified using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). IC50s were determined from cytotoxicity curves using a four-parameter curve fit software package (XLfit4).
|Concentrations||0~10 μ M|
|Incubation time||72 h|
|Animal models||female nu/nu CD-1 or SCID mice bearing tumor xenografts of NIH-3T3/LISN cells and Colo205 cells|
|Formulation||20% sulfobutyl ether β-cyclodextrin (ISP; pH 3.5)|
|Dosages||10, 30 and 60mg/kg once daily for 21 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 100 mg/mL|
Anaplastic Lymphoma Kinase: role in specific tumours, and development of small molecule inhibitors for cancer therapy.
Ardini E, et al. Cancer Lett. 2010 Dec 28;299(2):81-94. PMID: 20934803.
GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers.
Sabbatini P, et al. Mol Cancer Ther. 2009 Oct;8(10):2811-20. PMID: 19825801.
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