Flexible small molecular anti-estrogens with N,N-dialkylated-2,5-diethoxy-4-morpholinoaniline scaffold targets multiple estrogen receptor conformations.

Estrogen mediates various cellular processes including cell proliferation, differentiation, growth and mammary gland function. Estrogen Receptors (ERs) are expressed in 70% of breast cancers. Consequently, estrogen mediated ER signaling plays a critical role in breast cancer diagnosis, prognosis, and treatment. ERs are ligand-triggered transcription factors. However, in the absence of a cognate estrogenic ligand, ERs can be activated by a variety of other extracellular signals. Tamoxifen, an anti-estrogen that selectively targets ER, induces substantial regression of breast tumors and an increase in disease-free survival. 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. Library of compounds with substituted morpholinoaniline scaffold, a set of structurally divergent potential ER antagonists that fit the tamoxifen pharmacophore, were designed to target ER Ligand Binding Domain (LBD) and to recruit co-regulator proteins including BRCA1 over a range of conformational changes. Two of the lead compounds in the library, BR46 and BR47, were found to inhibit estrogen induced cell proliferation and cell viability. Discovery of novel lead molecules targeting ligand binding pockets of hER has provided structural clues toward the development of new breed of small molecule therapeutics for tamoxifen-resistant breast cancers and would complement already existent anti-estrogen therapy.