NVP-HSP990, as a novel oral Hsp90 inhibitor, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.
Patent: US20230218577A1 2023 Jul.
Use of heat shock protein inhibitors for the treatment of neurodevelopmental disorders
NVP-HSP990 purchased from AbMole
Cell Experiment | |
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Cell lines | GTL-16, BT-474, A549, NCI-H1975 and MV4;11 cell lines |
Preparation method | Cell proliferation and apoptosis assays Cells were treated with NVP-HSP990 or 17-AAG for 72 hours, and cell viability was determined by CellTiter-Glo Luminescent Cell Viability assay from Promega. Soft agar clonogenic assays with primary human tumors were conducted at Oncotest GmbH |
Concentrations | 0~1000nM |
Incubation time | 72 h |
Animal Experiment | |
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Animal models | Human tumor xenograft models GTL-16, NCI-H1975, BT474, and MV4;11 |
Formulation | 100% polyethylene glycol (PEG400) |
Dosages | a single dose of 15 mg/kg |
Administration | orally |
Molecular Weight | 379.39 |
Formula | C20H18FN5O2 |
CAS Number | 934343-74-5 |
Solubility (25°C) | DMSO 10 mM |
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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