Department of Pharmacology and Toxicology
Bioinformatics; Genomics and proteomics; Signal Transduction; Toxicology and Xenobiotics
Our laboratory seeks to understand hormone-triggered nuclear receptor signaling. Nuclear receptors are associated with various diseases including diabetes and cancer and the availability of several high resolution structures of their ligand binding domains make them attractive targets for drug discovery. Eight of the top 100 prescription drugs (accounting for about US $9 billion in sales) target a nuclear receptor. However, these drugs can cause a variety of side effects and some patients develop drug resistance.
Tamoxifen, a drug designed to selectively target the nuclear estrogen receptor which is present in 70% of breast cancer patients, induces substantial regression of breast tumors and an increase in disease-free survival. Tamoxifen binds directly to the ligand binding domain of estrogen receptor and regulates estrogen-mediated growth of breast cancer cells. Tamoxifen mimics estrogen effects in other tissues thereby providing some beneficial effects including reduced risk of osteoporosis. However, breast cancers that initially respond well to tamoxifen tend to develop resistance and resume growth despite the continued presence of the antagonist.
We specifically focus on protein interactions that regulate estrogen signaling by binding to estrogen receptors. Our objective is to identify the estrogen receptor conformation-sensing regions of the interacting proteins and to discover potential small molecule sensors using state-of-the art bioinformatics and structure-based discovery tools and use them to generate a new breed of small molecular therapeutics for breast cancer therapy.