819812-04-9

KW-2478是一种非Ansamycin的HSP90抑制剂，IC50为3.8 nM。Phase 1。

KW-2478 inhibits the binding of bRD to Hsp90α with IC50 of 3.8 nM. KW-2478 degradates the Hsp90 client proteins, including FGFR3 and IGF-1Rβand c-Raf-1. KW-2478 reduces the level of phosphorylated Erk1/2. KW-2478 induces apoptosis by cleavage of PARP, a substrate of caspase-3 In U266 cells,. KW-2478 has Time dependency of antiproliferative activity, consecutive drug exposure for at least 12 hours is necessary to to exert potent antitumor activity. KW-2478 downregulates the translocation products of IgH locus. KW-2478 inhibits the transcription of c-Maf and cyclin D1 genes by mainly suppressing the function of Cdk9. KW-2478 has potent and broad growth inhibitory activities against various cell lines, KW-2478 inhibites cancer cell growth in all cell lines, with EC50 of 101-252 nM, 81.4-91.4 nM and 120-622 nM for B-cell lymphoma, mantle cell lymphoma and multiple myeloma, respectively. KW-2478 also shows potent growth inhibitory activity in primary CLL and NHL cells with EC50 of 40-170 nM and 200-400 nM, respectively. .

KW-2478 suppresses tumor growth and induces the degradation of client proteins in tumors in NCI-H929 s.c. inoculated model at doses of 100 mg/kg or more. KW-2478 reduces both serum M protein and MM tumor burden in the bone marrow in OPM-2/GFP i.v. inoculated mouse model at doses of 100 mg/kg.

Target	Value
HSP90 ()	3.8 nM

KW-2478抑制bRD与Hsp90α的结合，IC50为3.8 nM。KW-2478降解Hsp90受体蛋白，包括FGFR3，IGF-1Rβ和c-Raf-1。KW-2478降低磷酸化Erk1/2的水平。在U266细胞中，KW-2478通过PARP裂解诱导细胞凋亡，PARP是caspase-3的一种底物。KW-2478具有时间依赖性抗增殖活性，需要连续药物暴露至少12小时以发挥有效的抗肿瘤活性。KW-2478下调IgH位点的易位产品。KW-2478通过主要抑制Cdk9的功能，抑制c-Maf和细胞周期蛋白D1基因的转录。 KW-2478对各种细胞系具有有效且广泛的抑制活性，KW-2478在所有细胞系中抑制癌细胞生长，对B细胞淋巴瘤，套细胞淋巴瘤和多发性骨髓瘤的EC50分别为101-252 nM，81.4-91.4 nM 和120-622 nM。KW-2478也在原代CLL 和NHL细胞中表现出有效的生长抑制活性，EC50分别为40-170 nM和200-400 nM。

在NCI-H929皮下注射接种的模型中，KW-2478在100 mg/kg或更高剂量下抑制肿瘤生长，并诱导肿瘤中受体蛋白降解。在OPM-2/GFP静脉注射接种的小鼠模型中，KW-2478在100 mg/kg剂量下降低骨髓中血清M蛋白质和MM肿瘤负担。