Rational Structure-Based Design of Anti-Breast-Cancer Drugs Targeting the erbB Family of Receptor Tyrosine

摘要

The new inhibitors of the ErbB2 tyrosine kinase domain are potential lead compounds against the most aggressive forms of breast cancer. To inhibit the catalytic domain of the receptor, we intended to crystallize the tyrosine kinase domain of the receptor and identify new lead candidates through a new virtual ligand screening procedure. The key component and prerequisite of this technology is the three-dimensional model of the target domain. This structure can either be obtained through an X%ay crystallography experiment, the best case scenario, or through model building by homology to other know structures. The next step is to improve the flexible docking procedure and perform it in a high throughput manner to predict the binders of the target of interest. After preliminary work on microcrystallization we expect a reasonable chance to crystallize the ErbB2 domain, even though it remains extremely challenging. Using the above technology, we are now ready to begin crystallization trials. We are ready to start docking studies using the models of ErbB2. These studies should first explain the pattern of cross-reactivity with other tyrosine kinase ligands. In the event that we obtain a crystal structure we will be ready to use it immediately for virtual ligand screening.