2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluoro-N-methylbenzamide

• ChemBase ID: 73188
• Molecular Formular: C27H29FN8O3
• Molecular Mass: 532.5693632
• Monoisotopic Mass: 532.23466505
• SMILES: n1c(nc2c(c1Nc1cccc(c1C(=O)NC)F)cc[nH]2)Nc1c(cc2c(c1)N(CC2)C(=O)CN(C)C)OC
• Canonical SMILES: CNC(=O)c1c(cccc1F)Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1cc[nH]2
• InChI: InChI=1S/C27H29FN8O3/c1-29-26(38)23-17(28)6-5-7-18(23)31-25-16-8-10-30-24(16)33-27(34-25)32-19-13-20-15(12-21(19)39-4)9-11-36(20)22(37)14-35(2)3/h5-8,10,12-13H,9,11,14H2,1-4H3,(H,29,38)(H3,30,31,32,33,34)
• InChIKey: HZTYDQRUAWIZRE-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydro-1H-indol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluoro-N-methylbenzamide
• IUPAC Traditional name: 2-{[2-({1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-6-fluoro-N-methylbenzamide
• Synonyms: GSK1838705A

Database IDs

• CAS Number: 1116235-97-2
• PubChem SID: 162038108
• PubChem CID: 25182616

CALCULATED PROPERTIES

• Acid pKa: 11.803308
• H Acceptors: 8
• H Donor: 4
• LogD (pH = 5.5): 1.8360311
• LogD (pH = 7.4): 3.8439407
• Log P: 4.061565
• Molar Refractivity: 146.3655 cm^3
• Polarizability: 54.47305 Å^3
• Polar Surface Area: 127.51 Å^2
• Rotatable Bonds: 8
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: IGF-1

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S2703

Research Area

• Description: Cancer

Biological Activity

• Description: 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
• Targets: IGF-IR; IR; ALK
• IC50: 2 nM; 1.6 nM; 0.5 nM ^[1]
• In Vitro: GSK1838705A potently and ATP-competitively inhibits IGF-IR and IR with ^appK_i values of 0.7 nM and 1.1 nM, respectively.In cells, GSK1838705A potently inhibits ligand-induced phosphorylation of IGF-IR and IR with IC50 of 85 nM and 79 nM, respectively. GSK1838705A shows the significant anti-proliferative effect in a panel of cell lines derived from solid and hematologic tumors such as L-82, SUP-M2, SK-ES and MCF-7 cells with EC50 of 24 nM, 28 nM, 141 nM and 203 nM, respectively. GSK1838705A shows an accumulation of MCF-7 and NCl-H929 cells predominantly in G1 (2N) phase of the cell cycle. GSK1838705A also inhibits ALK with K_i of 0.35 nM and supresses the proliferation of nucleophosmin (NPM)-ALK fusion cells with EC50 of 24-88 nM. GSK1838705A potently inhibits NPM-ALK phosphorylation in Karpas-299 and SR-786 cells, while has modest effect on STAT3 phosphorylation. ^[1]
• In Vivo: In NIH-3T3/LISN tumor-bearing mice, oral treatment of GSK1838705A (60 mg/kg) cause tumor growth inhibition by 77%, without significant weight loss. In COLO 205 tumor–bearing mice, inhibition of tumor growth by GSK1838705A (30 mg/kg) is 80%. Besides, the antitumor efficacy of GSK1838705A is also observed in mice bearing HT29 xenograft or BxPC3 xenograft. In mice, GSK1838705A (60 mg/kg) leads to a transient 2-fold increase in blood glucose levels by inhibiting IR signaling. 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. ^[1]
• Features: GSK1838705A is a small-molecule kinase inhibitor of IGF-IR and the insulin receptor.

Protocol

• Protocol: Kinase Assay ^[1]
• Kinase Assays: 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.
• Protocol: Cell Assay ^[1]
• Cell Lines: L-82, SUP-M2, SK-ES and MCF-7
• Concentrations: 0 to 10 μM
• Incubation Time: 72 hours
• Methods: Cells are seeded in 96-well dishes, incubated overnight at 37 °C, and treated with DMSO or GSK1838705A for 72 hours. For the NIH-3T3/LISN proliferation assays, cells are seeded on collagen-coated 96-well tissue culture plates and allowed to adhere for 24 hours. The medium is replaced with serum-free medium and the cells are treated with GSK1838705A for 2 hour. Cells are incubated for 72 hours 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 (XLfit4).
• Protocol: Animal Study ^[1]
• Animal Models: L-82, SUP-M2, SK-ES and MCF-7 cells are injected s.c. into the right flank of CD1 or SCID mice.
• Formulation: GSK1838705A is dissolved in 20% sulfobutyl ether β-cyclodextrin (ISP; pH 3.5).
• Doses: ≤60 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Sabbatini P, et al. Mol Cancer Ther. 2009, 8(10), 2811-2820.

REFERENCES

• Sabbatini P, et al. Mol Cancer Ther. 2009, 8(10), 2811-2820.