Onalespib (AT13387) is a non-geldanamycin inhibitor of HSP90, it inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. AT13387 showed a median EC(50) value of 41 nM and exhibited activity consistent with a cytotoxic effect in vitro. In vivo, antitumor activity of AT13387 was showed in both the imatinib-sensitive, GIST-PSW, xenograft model and a newly characterized imatinib-resistant, GIST430, xenograft model. AT13387 has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. While AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. A combination of AT13387 and imatinib treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies.
| Cell Experiment | |
|---|---|
| Cell lines | HCT116, A549, MCF-7, U266, PANC1, Huh-7, DU145, MES-SA, SKOV3, HL60, A375 and TFK-1 cells line |
| Preparation method | Proliferation assays. Cells were seeded into 96-well plates before the addition of compound in 0.1% (v/v) DMSO. GI50 were determined using a 10-point dose response curve for three cell doubling times. After compound incubation 10% (v/v), Alamar blue (Biosource International, Camarillo, CA, USA) was added, and cells were incubated for a further 4 h. Fluorescence was read at λex = 535 nm and λem = 590 nm. |
| Concentrations | 0~1 μ M |
| Incubation time | 48 or 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Athymic mice bearing NCI-H1975 xenografts |
| Formulation | 17.5% (w/v) hydroxypropyl-β-cyclodextrin |
| Dosages | 70 mg/kg on days 1, 4, 8, 12 and 16; 55 mg/kg on days 1, 4, 8, 12 and 16; or 90 mg/kg on days 1, 8 and 16. |
| Administration | intraperitoneally |
| Molecular Weight | 409.52 |
| Formula | C24H31N3O3 |
| CAS Number | 912999-49-6 |
| Solubility (25°C) | DMSO 25 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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