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The Design, Synthesis, and Biological Evaluation of Chimera Based Inhibitors of Hsp90, A Novel Approach to Breast Cancer Chemotherapeutics
In the past few years, the 90kDa heat shock proteins have become an increasingly important research area for the treatment of breast cancer. These ubiquitous, well-conserved proteins, account for 1-2% of all cellular proteins in most cells and are responsible for the maturation of proteins/receptors involved in cancer, including steroid hormone receptors, mutant p53, Src kinase, Raf, and telomerase, to name a few. Inhibition of Hsp90 results in the ubiquitination of bound client proteins, and subsequent proteolysis. Interaction of Hsp90-binding drugs geldanamycin (GDA) and radicicol (RDC) with the chaperone destabilizes these proteins in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells.
Most tumors become refractory to current hormonal therapies within a year of starting treatment. New targets for the development of therapeutics responsible for the maturation of several proteins involved in cancer are highly sought. GDA and RDC are excellent inhibitors of the Hsp90 folding process and one of the derivatives, 17-allylamino Geldanamycin has entered phase ¦© clinical trials for the treatment of breast cancer. Based on previously reported co-crystal structures of GDA and RDC, we have designed a chimera, which should be a more potent inhibitor of Hsp90 than the other three natural products.
Based on the structure-activity relationships, the proposal herein details the synthesis of several series of analogs of the GDA-RDC chimera in order to identify their potencies and optimize the structure-activity relationships under the guidance of bioassays. The potential problems may lie in the following aspect: Although little data are available, one might expect Hsp90-active agents to be toxic to normal cells. This can be overcome by structurally modifying the side chain of these molecules to decrease undesired toxicity and increase its selectivity for Hsp90 and subsequently breast cancer.
Hsp90 is the abbreviation for heat shock proteins with a molecular weight of 90kDa. They are common molecular chaperones (proteins that fold other proteins into active three-dimensional enzymes) found in higher living organisms. In vivo, Hsp90 interacts with proteins containing a high degree of tertiary structure. Hsp90 refolds denatured proteins and is also involved in their activation and maturation during cell growth. These client proteins include steroid hormone receptors, aryl hydrocarbon receptors, tumor suppressors, tyrosine and serine/threonine kinases and telomerase, which are all involved in breast cancer development and growth. Hsp90 has an ATP binding site in its structure and a carefully designed inhibitor can competitively bind to this ATP binding site, resulting in the loss of protein folding ability. Hsp90 expression is upregulated in tumor cells and thus Hsp90 is an excellent and new target for the development of antitumor compounds, especially breast cancer.
GDA and RDC are regarded as the most potent among all Hsp90 inhibitors reported, including Geldanamycin (GDA), Radicicol (RDC), Herbimycin A, and PU3. Structural modification of GDA gave rise to 17AAG, which has entered Phase ² clinical trials at the NIH and Sloan Kettering. Total synthesis and modification of GDA and RDC have been reported, but these molecules suffer from low solubility and toxicity unrelated to Hsp90 inhibition. Therefore, new inhibitors of Hsp90 that have increased solubility and selectivity are highly sought.
Based on computer-aided drug design, we propose several series of compounds that bind to Hsp90 perfectly in its three-dimensional crystal structure. We plan to synthesize all of the designed molecules and determine their activity by a high-throughput assay, which will allow us to provide a totally new class of antitumor compounds with potent activity against breast cancer. Recent clinical studies have shown that Hsp90-active agents are potent and people can eliminate side effects by shortening the duration of treatment, while maintaining excellent activity against breast cancer. In addition, they can also sensitize tumor cells to cytotoxic agents such as Taxol and Doxorubicin and thus require smaller amounts of other breast cancer drugs to be used and ultimately decrease side effects. So Hsp90 inhibitors have tremendous potential for the treatment of breast cancer.