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 Experiment | |
|---|---|
| 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). |
| Concentrations | 0~20 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| 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 |
| Administration | orally |
| Molecular Weight | 851.96 |
| Formula | C44H47F2N9O5S |
| CAS Number | 1089283-49-7 |
| Solubility (25°C) | DMSO 90 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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|---|
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IGF-I (24-41) (Insulin-like Growth Factor I (24-41)) is amino acids 24 to 41 fragment of IGF-I. |
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GIP, human is a peptide hormone consisting of 42 amino acids that also acts as a promoter of glucose-dependent insulin secretion and a weak inhibitor of gastric acid secretion. In addition, GIP, human acts as an enteric proinsulin hormone released by intestinal K cells in response to nutrient intake. |
| VMB-100
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| NBI-31772 hydrate
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| AZ12253801
AZ12253801 is an ATP-competitive IGF-1R tyrosine kinase inhibitor that shows ∼10-fold selectivity over the insulin receptor. AZ12253801 inhibits IGF-1R–driven proliferation in 3T3 mouse fibroblasts (transfected with human IGF-1R) with an IC50 of 17 nmol/L. The IC50 for epidermal growth factor receptor (EGFR)–driven proliferation is 440 nmol/L. Anti-tumor activity. |
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