生物活性
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.
化学数据
| 分子量 | 574.66 |
| 分子式 | C30H42N2O9 |
| CAS号 | 819812-04-9 |
| 纯度 | >98% |
| 溶解性（25°C） | DMSO 100 mg/mL |
| 储存和运输条件 | 固体粉末： -20°C 冷藏长期储存
常温运输及临时存放 |
实验操作 来自于公开的文献，仅供相同实验参考（如实验材料、目的不同，请参考其他文献）
| 细胞实验 |
|---|
| 细胞系 | OPM-2/GFP, KMS-11, RPMI 8226, and NCI-H929 cells |
| 方法 | 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 |
| 浓度 | 0.05 - 5 μM |
| 处理时间 | 3 days |
| 动物实验 |
|---|
| 动物模型 | NCI-H929 tumors s.c. inoculated in SCID mice, OPM-2/GFP i.v. inoculated mouse model |
| 配制 | sterile 0.9% sodium chloride solution |
| 剂量 | 25, 50 , 100 and 200 mg/kg |
| 给药处理 | Orally administrated once daily for 5 days |
不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 |
| 重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| 体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km系数 | 3 | 6 | 12 | 8 | 5 | 20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
储备液配制
以下数据基于产品分子量，对于特殊产品，请参照COA中的储备液配制条件和说明进行操作。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 1.7402 mL | 8.7008 mL | 17.4016 mL |
| 5 mM | 0.348 mL | 1.7402 mL | 3.4803 mL |
| 10 mM | 0.174 mL | 0.8701 mL | 1.7402 mL |
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