生物活性

• 描述KW-2478 is a nonansamycin Hsp90 inhibitor with IC50 value of 3.8nM. Compared with the previous Hsp90 inhibitor like 17-AAG, it overcomes limitations such as low water solubility and hepatotoxicity. Treatment with KW-2478 at concentration ranging in 0.1-10μM and time course in 12-72h led inhibition of OPM-2/GFP and NCI-H929 cell viability in a time- and dose-dependent manner. This may be associated with degradation of well-known Hsp90 client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and cyclin D1). KW-2478 at 3μM depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor in OPM-2/GFP, RPMI 8226, and U266 cells at 6h, 12h and 24h in a time-dependent manner. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. Administration of KW-2478 at 25mg/kg or 100mg/kg, i.v., twice daily for 5 days, suppressed tumor growth in NCI-H929 s.c. inoculated model, accompanied with the degradation of client proteins in tumors. Administration of KW-2478 at 100mg/kg, i.v., twice daily for 5 days showed a significant reduction of both serum M protein (measured on day 31, 38 and 45) and MM tumor burden in the bone marrow of a novel orthotopic MM model of i.v. inoculated OPM-2/green fluorescent protein.