Discovery and Test of Small Molecule Inhibitions of XIAP as Potential Novel Therapy for the Treatment of Breast Cancer

摘要

The inhibitors of apoptosis protein (IAP) are intrinsic cellular negative regulators of apoptosis. The X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor in IAP family, which is highly expressed in most of the widely studied breast cancer cell lines. The mitochondrial protein Smac is a negative regulators of XIAP that competitively binds to a binding pocket on the BIR3 domain of XIAP and disrupts caspase-9 binding to XIAP. Using the 3D structure of XIAP, we have performed a structure-based database screening of large chemical databases and discovered several non- peptide small molecule inhibitors of XIAP. The most potent compound among them, SMXI-56, binds to the XIAP BIR3 protein with an affinity similar to that of the natural Smac peptide in a fluorescence polarization-based binding assay. The NMR HMQC analysis confirmed that SMXI-56 interacts with several crucial residues in the XIAP BIR3 domain where Smac and caspsase-9 bind. SMXI-56 inhibits cell growth and induces apoptosis in breast cancer cells with high levels of XIAP, but has a minimal effect on normal breast cells with low levels of XIAP. This work demonstrates that the virtual database screening combined with biological activity tests can identify potential inhibitors of XIAP for treatment of breast cancer.