Transcriptional Control of Breast Cancer: Molecular Lego and Combinatorial Libraries

摘要

Overexpression of the HER-2/neu oncogene is common in many types of cancer, including breast cancer, and correlates well with poor overall survival rates in cancer patients. Thus, effective methods for controlling the expression of HER-2/neu could prove clinically useful. Previous experimental data have indicated that binding of the PEA3 protein to a 6- bp-long sequence on the HER- 2/neu promoter down-regulates the activity of the promoter and subsequently and preferentially inhibits the growth of HER-2/neu-overexpressing cancer cells. Our research was aimed at developing small molecules able to bind 6-bp-long DNA sequences with high affinity and selectivity in the hopes that such molecules would bind to a promoter region of HER-2/neu and selectively inhibit the growth of HER-2/neu-overexpressing cells. Using a modular approach that we developed previously, we devised a novel chemical strategy and new building block that allow for greater flexibility in designing and preparing structurally diverse DNA binding agents. This versatile building block, a 3-amino-4-thio-L-lyxo- hexopyranose, was designed to localized in the minor groove and to selectively react with more building blocks and linkers than ever before. We demonstrated its usefulness by designing and synthesizing DNA binding agents aimed at covering 6-bp-long sequences.