Theoretical study of the intermolecular recognition mechanism between Survivin and substrate based on conserved binding mode analysis.

Survivin is the smallest member of IAP (inhibitor of apoptosis protein) family, which plays important roles in both mitosis and apoptosis. It has become an attractive drug target due to its overexpression in many human cancers. Survivin has been proven to bind to Smac/DIABLO protein that indirectly inhibits apoptosis. Meanwhile, it is the key subunit of chromosome passenger complex (CPC) which bind to the N-terminal tail of phosphorylated histone H3T3ph during mitosis. Up to now, Survivin directly targeting inhibitor has yet to merge since the difficulty of disrupting the protein-protein interactions (PPIs) between Survivin and its substrate proteins. Nevertheless, currently known binding partners of Survivin provide crucial information about conserved recognition mechanism, which can assist in the detection of some uncharted substrates and also the Survivin inhibitors. Herein, we adopted a method that using four substrates to analyze the common binding mode of Survivin. To accomplish this, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized born surface area (MM-GBSA) binding free energy calculations and energy decomposition were carried out to assess the binding affinity and per-residue contributions. We found that there are two anchor sites of Survivin responsible for maintaining the binding conformation and one sub-pocket for intermolecular recognition. The results of this study synthetically describe the binding mechanism and provide valuable guidance for rational drug design of PPI inhibitor.

Novel pyrrolopyrimidines as Mps1/TTK kinase inhibitors for breast cancer.

New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC50 values ranging from 0.05 to 1.0µM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC50 values from 0.356µM to 0.809µM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.