Structure-Based Design, Synthesis and Testing of Non-Peptide, Cell- Permeable, Potent Small Molecule Smac Mimetics as a New Therapy for Prostate Cancer. Revision
(Englisch)
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XIAP (X-linked inhibitor of apoptosis protein) is a promising new therapeutic target for the design of an entirely new class of effective and non- toxic cancer therapy to improve survival and quality of life of prostate cancer patients. New therapies targeting XIAP may prove to be especially effective to overcome apoptosis-resistance of prostate cancer cells. Using a powerful computational structure-based design strategy, we have designed and synthesized new, non-peptide, cell-permeable small-molecule inhibitors of XIAP. The most potent inhibitors bind to XIAP with nanomolar affinities and are highly potent in inhibition of cell growth in androgen-independent human prostate cancer cell lines. Furthermore, such inhibitors are highly effective in enhancing the activity of other anticancer drugs in human prostate cancer cells. Importantly, these inhibitors have a low toxicity to normal cells. Taken together, our studies have led to the discovery of highly promising small-molecule inhibitors of XIAP. Further optimization of these promising lead compounds may ultimately lead to the development of a new class of anticancer drugs for the treatment of advanced human prostate cancer.
Structure-Based Design, Synthesis and Testing of Non-Peptide, Cell- Permeable, Potent Small Molecule Smac Mimetics as a New Therapy for Prostate Cancer. Revision