Small molecule inhibitors: novel probes of progesterone receptor action

progesterone;steroid receptor;small molecule inhibitor;theophylline;structure activity relationship

Aninye, Irene

关键词: progesterone;    steroid receptor;    small molecule inhibitor;    theophylline;    structure activity relationship;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/31017/Aninye_Irene.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The progesterone receptor (PR) is an important member of the nuclear receptor superfamily of transcription regulatory proteins. It plays vital roles in a diverse set of biological processes, from homeostasis to reproduction. PR’s major function involves binding of liganded receptor to DNA and regulating the expression of progesterone-responsive genes. Much of what we have learned about PR action has been based on studies using progestins and anti-progestins that bind in the receptor’s ligand binding pocket. PR-specific antagonists can potentially serve as useful treatments for endometriosis, uterine fibroids, and breast cancer. We have identified a set of small molecules that uniquely act outside of PR’s ligand-binding pocket and selectively inhibit PR activity in intact cells. These small molecules inhibit PR-mediated induction of the mouse mammary tumor virus (MMTV)-luciferase reporter and endogenous alkaline phosphatase activity in T47D cells with IC50s in the low micromolar range. They inhibit PR with limited cross-reactivity for inhibiting other steroid receptors, estrogen receptor (ER), glucocorticoid receptor (GR), and androgen receptor (AR). Our in vitro studies show that these inhibitors do not act by blocking PR binding to the progesterone response element on DNA. One class of inhibitors described here act, in part, by altering the nuclear localization of activated receptor, leading to reduced DNA binding in cells. A different class of small molecules does not reduce DNA binding, but preferentially inhibits PR-mediated gene transactivation. Identifying novel sites and modes of action of small molecule inhibitors of progesterone receptor will be useful in dissecting details of the mechanisms of PR action. These sets of noncompetitive inhibitors that demonstrate specificity for PR over GR show promise in their ability to distinguish between the roles of PR and GR-mediated gene transcription, and have long term potential for therapeutic development.