Strategies of Discovering Small Molecular Drugs Targeting Growth Factor Heregulin
Abstract
Heregulin (HRG) constitutes the HRG subfamily of EGF-related peptides that were isolated from breast cancer cell line MDA-MB-231, and ras-transformed Rat-1 fibroblasts. HRG can stimulate proliferation and may function as an autocrine growth factor in transformed mammary epithelial cells. Stable expression of HRG via transfection leads tumor formation in nude mice and might perform a role in progression to estrogen-independent tumor growth. Furthermore, HRG induces in vivo lobuloalveolar development of mammary gland, and in MMTV-HRG transgenic mice, HRG induces mammary adenocarcinoma, and hyperplasia. Clinically, elevated expression of HRG play a role in breast cancer growth and progression and is associated with less favorable disease outcome. We have used a structure-based strategy towards the discovery of small molecules as potential HRG antagonists. Small, non-peptidal molecules which mimics the 3D structure of HRG binding domain could specifically block ligand receptor-binding. Lead compound SMA1 demonstrated activity as specific antagonists of HRG in receptor binding competition, HRG-induced phosphorylation assays and HRG-dependent cell proliferation assays. Inhibition of HRG- induced phosphorylation or cell growth can be reversed by addition of extra amount of HRG, suggesting the compound SMA1 may function as HRG antagonist. The discovery of compounds represents an important step in the development of the small molecule, HRG antagonists as potential clinical candidates in the prevention and treatment of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA403690
Entities
People
- Dajun Yang
Organizations
- Georgetown University