Mechanism of action of a novel series of inhibitors of the Hsp90 molecular chaperone

摘要: 3994 Inhibition of the molecular chaperone Hsp90 is a highly attractive anticancer strategy because its potential to provide combinatorial blockade multiple oncogenic pathways and simultaneous antagonism all malignant hallmarks cancer. Although geldanamycin analogue 17AAG shows promise in early clinical trials, natural product inhibitors have liabilities that would best be overcome by identifying synthetic small molecule agents. We previously described discovery high throughput screening an lead compound designated CCT018159 (Aherne et al Proc. AACR 44 Abstract #4002). now report biological properties series closely related analogues this diarylpyrazole structure. Improved activity potency has been observed against yeast human recombinant ATPase using malachite green colorimetric assay for inorganic phosphate. Anticancer cell culture demonstrated range tumour types, including HCT116 colon carcinoma as well various melanoma lines. The signature inhibition, defined details proteomic gene expression microarray analysis, confirmed western blotting ELISA elevation Hsp70 Aha1 depletion C-Raf-1, ErbB2 phospho-ERK1/2, together with other client proteins co-chaperones. Cell-line dependent G1 G2M arrest dual-stain Hoechst-propidium iodide flow cytometry apoptosis sub-G1 peak, morphology, PARP caspage cleavage. Activity retained P-glycoprotein positive line made resistant doxorubicin also cells platinum Pharmacokinetic are promising, glucuromide conjugation resorcinol ring being major clearance mechanism. In summary, compounds significant development broad spectrum activity. Supported Cancer Research UK, Wellcome Trust Vernalis .