Background
GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC50s of 2.0 and 1.6 nmol/L, respectively.
IGF-1R is a transmembrane receptor which is activated by insulin-like growth factor 1 and by a related hormone IGF-2. This protein plays important role in the regulation of development. The insulin receptor is also a transmembrane receptor that is activated by insulin, IGF-1 and IGF2. This receptor is involved in insulin signaling pathway and plays an essential role in the regulation of glucose homeostasis.
GSK1838705A obstructs the in vitro expansion of cell lines got from strong and hematologic malignancies, including numerous myeloma and Ewing's sarcoma, and hinders the development of human tumor xenografts in vivo. In spite of the inhibitory impact of GSK1838705A on insulin receptor, insignificant effects on glucose homeostasis were seen at efficacious dosages. GSK1838705A represses the anaplastic lymphoma kinase (ALK), which drives the distorted development of anaplastic substantial cell lymphomas, some neuroblastomas, and a subset of non–small cell lung growths.
GSK1838705A restrains ALK, with an IC50 value of 0.5 nM, furthermore, causes complete relapse of ALK-ward tumors in vivo at very-endured measurements. GSK1838705A arrives for a promising antitumor agent for helpful use in human growth.
Reference:
[1].? Sabbatini P, et al. GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther. 2009 Oct;8(10):2811-20.
Protocol
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Kinase experiment:
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Baculovirus-expressed glutathione S-transferase–tagged proteins encoding the intracellular domain of IGF-IR (amino acids 957–1367) and IR (amino acids 979–1382) are used for determinations of IC50s by a homogeneous time-resolved fluorescence assay. A filter binding assay is used for appKi determinations using activated IGF-IR and IR kinases. Expanded kinase-selectivity profiling of GSK1838705A is carried out by screening the compound in the KinaseProfiler panel[1].
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Cell experiment:
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in vitro studies[1].--> Cells are 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 are seeded on collagen-coated 96-well tissue culture plates and allowed to adhere for 24 h. The medium is replaced with serum-free medium and the cells are treated with GSK1838705A for 2 h. Cells are incubated for 72 h after addition of IGF-I (30 ng/mL). Cell proliferation is quantified using the CellTiter-Glo Luminescent Cell Viability Assay. IC50s are determined from cytotoxicity curves using a four-parameter curve fit software package[1].
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Animal experiment:
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Mice: Exponentially growing cells are implanted s.c. into the right flank of 8- to 12-wk-old female nu/nu CD-1 or SCID mice. Mice are dosed p.o. with the formulating vehicle or GSK1838705A. Mice are weighed and tumors measured by calipers twice weekly. Tumor volumes are calculated[1]
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参考文献:
[1]. Sabbatini P, et al. GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers.Mol Cancer Ther. 2009 Oct;8(10):2811-20.
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