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KW-2478

Cat. No. M3563
KW-2478 Structure
Size Price Availability
5mg USD 190  USD190 Out of stock
10mg USD 260  USD260 Out of stock
50mg USD 720  USD720 Out of stock
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Quality Control & Documentation
Biological Activity

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.

Protocol (for reference only)
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
Chemical Information
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
Conversion of different model animals based on BSA (PMID: 27057123)
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.

References

[1] Hui-Jin Li, et al. Anti-NSCLC activity in vitro of Hsp90 N inhibitor KW-2478 and complex crystal structure determination of Hsp90 N-KW-2478

[2] Xiaomin Chang, et al. Effect of Hsp90 Inhibitor KW-2478 on HepG2 Cells

[3] J Cavenagh, et al. A phase I/II study of KW-2478, an Hsp90 inhibitor, in combination with bortezomib in patients with relapsed/refractory multiple myeloma

[4] K Yong, et al. Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies

[5] T Ishii, et al. Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib

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