Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases

摘要

The overall goal of this US Army Breast Cancer Grant entitled 'Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases' was to develop novel methods to synthesize by combinatorial methods libraries of small molecules and to test small molecules for their ability to inhibit protein phosphatases thought to be important for the development of breast cancer. During the past three years we have synthesized more than 1,000 novel small molecules designed on natural products. These pharmacophores were used to build libraries by combinatorial methods. We tested more than 11,000 existing or new compounds for their ability to inhibit Cdc25 in vitro. Several of the new compounds are potent partial competitive inhibitors of Cdc25. We have established that these compounds also inhibit Cdc25 within cells and have the ability to inhibit the growth of human breast cancer MCF-7 and MDA-MB-231 cells. The selectivity of these inhibitors against other protein phosphatases has been established and one of the compounds has been tested in vivo and been shown to have antitumor activity. These results suggest that our approach to the design and identification of novel therapeutics agents directed against human breast cancer is promising.