GSK1904529A, selectively inhibits IGF-IR and IR with IC50s of 27 and 25 nmol/L, respectively. It is a promising candidate for therapeutic use in solid and hematologic cancers. IC50s for GSK1904529A in tumor cell lines ranged from 35 nmol/L to >30 umol/L. The tumor histologic types showing the greatest sensitivity to this compound were Ewing’s sarcoma and multiple myeloma, where IC50s in three of five Ewing’s sarcoma cell lines were <100 nmol/L and IC50s in five of eight multiple myeloma cell lines were <200 nmol/L.
|Cell lines||NCI-H929, NIH-3T3/LISN, COLO 205, HT29, and BxPC3 cells|
|Preparation method||Cell proliferation assays.
Cells were seeded in 96-well dishes, incubated overnight at 37°C, and treated with various concentrations of GSK1904529A 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 tissue culture medium was replaced with serum-free medium and the cells were treated with DMSO or GSK1904529A for 2 h. IGF-I (30 ng/mL) was added and the cells were incubated at 37°C for 72 h. Cell proliferation was quantified using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) following the manufacturer's recommendations. IC50 values were determined by using a four-parameter curve fit software package (XLfit4).
|Incubation time||72 h|
|Animal models||NIH-3T3/LISN, COLO 205, HT29, and BxPC3 cells tumour xenograft model in female nu/nu CD-1 athymic mice|
|Formulation||formulated in 20% sulfobutylether-β-cyclodextrin (pH 3.5; ISP)|
|Dosages||30 mg/kg once or twice daily for 21 d|
|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 90 mg/mL|
Antitumor activity of GSK1904529A, a small-molecule inhibitor of the insulin-like growth factor-I receptor tyrosine kinase.
Sabbatini et al. Clin Cancer Res. 2009 May 1;15(9):3058-67. PMID: 19383820.
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