Chemical Probes of Rapid Estrogen Signaling in Breast Cancer Treatment and Chemoprevention

摘要

The goal of this project was to design new chemical tools to selectively probe the molecular mechanisms of action of rapid estrogen receptor action and their relevance to breast cancer drugs like tamoxifen. Over the course of the project, we synthesized and tested approximately 15 new estrogen receptor modulators, some with novel activity in terms of both classic transcriptional and rapid response modulation. We discovered that the structure activity relationship for some rapid estrogen responses is different than the SAR required for transcriptional regulation, but that rapid responses could not be separated from the transcriptional modulation. We synthesized a novel metabolite of tamoxifen, called endoxifen, which appears to be the major bioactive metabolite of tamoxifen in women. This work also resulted in a letter to the FDA concerning possible drug interactions between tamoxifen and women taking certain antidepressants. We also made a new polymer-based conjugate of 4- hydroxytamoxifen that not only shows great uptake into ER positive breast cancer cells, but also shows antiproliferative activity against antiestrogen sensitive and antiestrogen- resistant breast cancer cell lines. We are currently trying to translate this unexpected finding into the design of new experimental therapeutics for the treatment of tamoxifen-resistant breast cancer, an urgent need for breast cancer patients.