GSK1838705A is an effective IGF-1R inhibitor (IC50: 2.0 nM), modestly potent to IR (IC50: 1.6 nM) and ALK (IC50: 0.5 nM), respectively, and little inhibition to other protein kinases.

ALK:0.5 nM, IGF-1R:2 nM, Insulin receptor:1.6 nM

In mice carrying COLO 205 tumors, GSK1838705A (30 mg/kg) inhibits 80% of tumor growth. Additionally, GSK1838705A demonstrates antitumor activity in mice with HT29 or BxPC3 xenografts. In mice with NIH-3T3/LISN tumors, GSK1838705A (60 mg/kg, p.o.) suppresses 77% of tumor growth without significant weight loss. It also momentarily doubles blood glucose levels by inhibiting IR signaling at a dose of 60 mg/kg. Furthermore, GSK1838705A (60 mg/kg) inhibits growth in established Karpas-299 xenografts by 93%, with no adverse effects on rat weight.

GSK1838705A effectively inhibits the phosphorylation of IGF-1R (IC50: 85 nM) and IR (IC50: 79 nM) induced by ligands in cells. It demonstrates significant antiproliferative effects on various cell lines derived from solid and hematological tumors, such as L-82, SUP-M2, SK-ES, and MCF-7 (EC50: 24/28/141/203 nM). GSK1838705A induces the accumulation of MCF-7 and NCI-H929 cells in the G1 (2N) phase of the cell cycle. Additionally, it inhibits ALK (Ki: 0.35 nM) and the proliferation of cells expressing the NPM-ALK fusion protein (EC50: 24-88 nM). GSK1838705A significantly suppresses the phosphorylation of NPM-ALK in Karpas-299 and SR-786 cells, though it exhibits moderate effects on the phosphorylation of STAT3.

Kinase Assays: Baculovirus-expressed glutathione S-transferase-tagged proteins encoding the intracellular domain of IGF-1R (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-1R and IR kinases. Expanded kinase-selectivity profiling of GSK1838705A is carried out by screening the compound in the KinaseProfiler panel.

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(Only for Reference)