Structure-Based Design, Synthesis and Testing of Non-Peptide, Cell-Permeable, Potent Small Molecule Smac Mimetics as a New Therapy for Prostate Cancer
Annual rept. 15 Feb 2004-14 Feb 2005
MICHIGAN UNIV ANN ARBOR
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XIAP is a promising new molecular target for the design of an entirely new class of 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 a new class of non-peptide small-molecule inhibitor of XlAP. The most potent compound binds to XlAP with a low nanomolar affinity and is potent in inhibition of cell growth in androgen-independent human prostate cancer cell lines. Furthermorn it is highly potent and effective in enhancing the activity of other anticancer drugs in human prostate cancer cells. Importantly, it has a low toxicity to normal cells. These compounds represent promising leads for further optimization toward our ultimate goal of developing a new class of anticancer drugs by targeting XlAP and promoting apoptosis in cancer cells.
- Anatomy and Physiology
- Medicine and Medical Research