Strategies of Discovering Small Molecule Drugs Targeting Growth Factor Heregulin

摘要

Heregulin (HRO) constitutes the HRG subfamily of EOF-related peptides that were isolated from breast cancer cell line MDA-MB-23 1, and ras-transformed Rat-i 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, HRO induces mammary adenocarcinoma, and hyperplasia. Clinically, elevated expression of HRO 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 SMA 1 demonstrated activity as specific antagonists of HRO in receptor binding competition, HRG-induced phosphorylation as says and HRO-dependent cell proliferation assays. Inhibition of HRO- induced phosphorylation or cell growth can be reversed by addition of extra amount of HRG, suggesting the compound SMA 1 may function as HRG antagonist. The discovery of compounds represents an important step in the development of the small molecule, HRO antagonists as potential clinical candidates in the prevention and treatment of breast cancer.