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KW-2478 is a novel non-ansamycin potent Hsp90 inhibitor with an IC50 of 3.8 nM. KW-2478 is a novel non-purine analogue antagonist for Hsp90. KW-2478 suppressed the binding of bRD to HSP90α in concentration-dependent manner. KW-2478 indicated a potent anti-cancer activity both in vitro and in vivo. KW-2478 clearly prevented cancer cell growth in all cell lines, with EC50 of 101-252, 81.4-91.4 and 120-622 nM for B-cell lymphoma, mantle cell lymphoma and multiple myeloma, respectively. KW-2478 also showd potent growth inhibitory activity in primary CLL (n=3) and NHL (n=2) cells with EC50 of 40-170 nM and 200-400 nM, respectively. KW-2478 depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. In NCI-H929 s.c. inoculated model, KW-2478 displayed a significant inhibition of tumor growth and induced the degradation of client proteins in tumors.
| Cell Experiment | |
|---|---|
| Cell lines | OPM-2/GFP, KMS-11, RPMI 8226, and NCI-H929 cells |
| Preparation method | To measure the IC50, plating OPM-2/green fluorescent protein (GFP) cells, KMS-11 cells, OPM-2/GFP and other cells into 96-well plates and treating them with KW-2478. 72 hours of cultivation later, using Cell Proliferation Reagent WST-1 to determine cell viability . WST reagent is added to the wells, followed by incubation for 4 hours at 37 °C. After that, measuring the absorbance at 450 nm with reference at 650 nm with a microplate spectrophotometer. To examine time dependency of antiproliferative activity of KW-2478, plating the cells into 96-well V-bottomed plates and treating with KW-2478. After 0 hour and at intervals from 3 to 72 hours at 37 °C, the supernatant is aspirated. After drug-free medium is added to the wells, the supernatant is aspirated again. Finally, adding drug-free medium to the wells, and the plates are further incubated for the remainder of the 72-hour period, followed by measurement of cell viabil |
| Concentrations | 0.05 - 5 μM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | NCI-H929 tumors s.c. inoculated in SCID mice, OPM-2/GFP i.v. inoculated mouse model |
| Formulation | sterile 0.9% sodium chloride solution |
| Dosages | 25, 50 , 100 and 200 mg/kg |
| Administration | Orally administrated once daily for 5 days |
| Molecular Weight | 574.66 |
| Formula | C30H42N2O9 |
| CAS Number | 819812-04-9 |
| Solubility (25°C) | DMSO 100 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
[2] Xiaomin Chang, et al. Effect of Hsp90 Inhibitor KW-2478 on HepG2 Cells
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