90 kDa heat shock proteins belong to a family of chaperones that regulate intracellular functions and are required for the refolding of denatured proteins following heat shock, as well as the conformational maturation of a large number of key proteins involved in cellular processes. Inhibitors of Hsp90 disrupt the protein folding process, resulting client protein degradation via the ubiquitin proteasome pathway. Hsp90 multi-protein complex in tumor cells exhibits a higher affinity for N-terminal ligands and malignant cell and highly dependent upon the Hsp90 protein folding machinery for cell survival. Inhibition of Hsp90 could result in combination of disruption of multiple signaling pathways in which is important for the tumor cell survival and bring a potential method for carcer treatment.In the past several years, based on Hsp90 crystal structure, we found a series of new Radicicol derived compounds (Fig 1) which show good potency in Hsp90 binding and inhibitory effect on human cancer cell growth in vitro, indicating further application in anti-tumor drug development. Recently, several Phase II-IIIclinical trial candidates showed some side effect on inducing glaucoma problems. Related with our Radicicol derived compounds, we found some synthesized compounds with lass Hsp90 inhibition effect ion could kick out this concerning based on rabbit model. The work is supported by NSFC 30973639,21310005081323and2012G0021840

Structure-based design, synthesis, and biological activity study of Hsp90 inhibitors

247th National Meeting (2014)

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