Project Name

Screen for estrogen receptor coactivator binding inhibitors and potentiators to modulate estrogen action

ASSAYS:

  • ERα Coactivator Binding Inhibitors
  • ERα Coactivator Binding Activators
  • ERβ Coactivator Binding Inhibitors
  • ERβ Coactivator Binding Activators

Principal Investigator/Assay Provider:

John A. Katzenellenbogen, PhD, University of Illinois Urbana-Champaign

 

Project Goal

Identify receptor-specific coactivator binding inhibitors and potentiators to modulate gene activation through the estrogen receptors ERa and ERb

Assay Type:

HTR-FRET

 

Project Description

Coactivator binding inhibitors (CBIs):
The overall aim of these assays is to identify novel compounds that can act as effective coactivator binding inhibitors (CBIs) to block gene activation through the estrogen receptors, ERa and ERb, by directly inhibiting their interaction with important coregulator proteins. The ERs are well validated targets for women’s health and breast cancer prevention and treatment. The CBIs are not targeted at the traditional site on the ERs, namely, the ligand binding pocket; rather, their target is a hydrophobic groove through which the ERs interact with the coactivator proteins of the p160 family, the steroid receptor coactivators SRC1 and SRC3, critical mediators of estrogen signaling and the regulation of gene transcription by the ERs. By blocking estrogen signaling through ERa and ERb by direct competition with their binding to SRC1 and SRC3 in the hydrophobic groove rather than indirectly by competitive ligand-based antagonism within the ligand binding pocket, the assay providers hypothesize that a more complete blockade of estrogen action may be achieved, which could possibly overcome the development of resistance to endocrine therapy that typically occurs in the treatment of breast cancer both with antiestrogens and aromatase inhibitors.

Coactivator binding potentiators (CBPs):
The overall aim of these assays is to identify novel compounds that can act as effective coactivator binding potentiators (CBPs) of the estrogen receptors, ERα and ERβ. Menopause is associated with the onset of hot flashes, night sweats, mood changes, and urogenital atrophy, which many women find distressing enough to seek medical management for relief. Estrogens in the form of hormone therapy (HT) have been the standard treatment for menopausal symptoms for decades. Although HT is the most effective treatment for hot flashes, the Women’s Health Initiative (WHI) trial found that the combination of estrogen and progestin increases a woman's risk for heart disease, stroke, breast cancer, venous thromboembolic events, and dementia and does not improve quality of life indices such as emotional and sexual functioning and vitality. The adverse effects of HT created a large unmet need for selective estrogen receptor modulators (SERMs) as an effective alternative to estrogens in HT for menopausal symptoms. ERa or ERb selective agonists might be a safer alternative for long-term HT.

Assay Description:

This assay is an HTR-FRET assay that measures the interaction between the ligand binding domain (LBD) of ERa indirectly labeled with a long-lifetime europium chelate (FRET donor) and a Cy5-labeled sequence of SRC1 (FRET acceptor). The goal of this assay is to identify library compounds that disrupt or enhance the ER-SRC1 interaction.