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 Jan 2005-14 Jan 2006
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 database screening, we have discovered the only class of non-peptide small-molecule inhibitor of XIAP. Through computational design and chemical modifications, we have now obtained very potent small-molecule inhibitors of XIAP. They bind to XIAP with nanomolar affinities and effectively inhibit cancer cell growth in PC-3 human prostate cancer cell line. These compounds represent promising leads for further optimization toward our ultimate goal of developing a new class of anticancer drugs by targeting XIAP and promoting apoptosis in cancer cells.
- Medicine and Medical Research