Antigene Strategy in Breast Cancer Therapy: Rationales for Direct Targeting of erbB2/Her2 DNA with Polymides

We have developed a complex computational approach to identify the best fragments within erbB2HER2neu promoter suitable for targeting with a novel class of Pyrrole-Imidazole containing polyamide molecules and to design the most potent polyamide binders to these targets. The target identification takes into account the most important regulatory elements in the promoter whole-genome specificity of the targets and possible mutations in the target sequences. We have designed a variety of conformationally feasible polyamide molecules, matching the best candidate 11-14 bp DNA target sequences. We have developed an algorithm, based on the 1CM molecular modeling package, to build all-atom 3D models of various polyamide-DNA complexes with different sequences and polyamide topology, and to predict polyamide-DNA binding constants. We continue to improve and benchmark the algorithm with new experimental results, such as a series of experimentally measured affinity data and NMR structural data. This fast and reliable algorithm will help to identify the best polyamide candidate antigene inhibitors to be synthesized and tested during the next stage of the project.