GSK1838705A

Names

[ Name ]:
GSK1838705A

[Synonym ]:
Benzamide, 2-[[2-[[1-[2-(dimethylamino)acetyl]-2,3-dihydro-5-methoxy-1H-indol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methyl-
2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide
GSK1838705A
2-[(2-{[1-(N,N-Dimethylglycyl)-5-methoxy-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide
pyrrolo[2,3-d]pyrimidine deriv.,40
CS-0695
cc-268

Biological Activity

[Description]:

GSK1838705A is a potent and reversible IGF-IR and the insulin receptor inhibitor with IC50s of 2.0 and 1.6 nM, respectively. It also inhibits ALK with an IC50 of 0.5 nM.

[Related Catalog]:

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> ALK

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> IGF-1R

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Insulin Receptor

Research Areas >> Cancer

[Target]

IC50: 2.0 nM (IGF-IR), 1.6 nM (insulin receptor), 0.5 nM (ALK)[1]

[In Vitro]

In cellular phosphorylation assays, GSK1838705A potently inhibits IGF-IR and insulin receptor phosphorylation with IC50s of 85 and 79 nM, respectively. appKi values are 0.7 nM for IGF-IR and 1.1 nM for insulin receptor using the filter binding assay. GSK1838705A inhibits the proliferation in a panel of cell lines derived from solid and hematologic tumors. The EC50s of GSK1838705A range from 20 nM to >8 μM, but are <1 μM in most multiple myeloma and Ewing's sarcoma cell lines[1].

[In Vivo]

GSK1838705A shows robust antitumor activity in animal xenograft models. Tumor types likely to respond to GSK1838705A include multiple myeloma and Ewing's sarcoma, as well as ALK-driven tumors (e.g., ALCL, NSCLC, and neuroblastoma). A single oral dose of GSK1838705A at 0.1 and 0.3 mg/kg results in 35% and 65% inhibition of IGF-IR phosphorylation, respectively, whereas doses ≥1 mg/kg results in complete inhibition of ligand-induced IGF-IR phosphorylation[1].

[Kinase Assay]

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].

[Cell Assay]

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].

[Animal admin]

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]

[References]

[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.

[2]. 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.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Molecular Formula ]:
C₂₇H₂₉FN₈O₃

[ Molecular Weight ]:
532.569

[ Exact Mass ]:
532.234680

[ PSA ]:
137.46000

[ LogP ]:
1.32

[ Appearance of Characters ]:
white to light brown

[ Index of Refraction ]:
1.700

[ Storage condition ]:
?20°C

[ Water Solubility ]:
DMSO: soluble20mg/mL, clear

MSDS

Click to get detail MSDS

Safety Information

[ RIDADR ]:
NONH for all modes of transport

GSK1838705A

Names

Biological Activity

Chemical & Physical Properties

MSDS

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Safety Information

Synthetic Route

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Precursor & DownStream

Precursor

DownStream