HSP90 (heat shock protein 90) is a cellular ubiquitous molecular chaperone responsible for promoting the conformational mutation and stabilization of several client oncoproteins, including Met, B-Raf, p53, Akt, and Kit, function of which is required by tumor cells to maintain appropriate client protein expression necessary for proliferation and survival. Luminespib is a potent HSP90 inhibitor with IC50 value of 21nM (measured by a fluorescence polarization (FP) competitive binding assay). Treatment with luminespib dose-dependently led to decreased of protein level of its client protein Her2 and Raf-1 and increased HSP72 at 16nM or 32nM for 24h and anti-proliferation with GI50 of 16nM in HCT116 cells. In vivo study showed that luminespib had a comparatively high tumor concentration with tumor/plasma ratio of 2.3 at a dose of 4mg/kg. Intraperitoneal injection of luminespib at dose of 50mg/kg, q.d., for 12 days achieved almost 50% tumor growth inhibition in HCT116 human colon carcinoma xenografts, with decreased Raf-1, Her2 and increased HSP72 at 6h after the final dose, which showed the pharmacodynamic of it[1].
作用机制
Luminespib can bound to the ATP binding site of human Hsp90-alpha.[1]
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