EM-652: A Third-Generation SERM with Pure Antiestrogenic Activity in Mammary and Endometrial Tissues

Breast cancer ranks as the top cancer among women and is a leading cause of cancer-related deaths. The role of estrogens in the progression of this disease is significant, prompting extensive research into methods that can hinder estrogen production and its effects. Tamoxifen, an antiestrogen, is a widely utilized treatment for breast cancer, but its mixed effects necessitate the development of antiestrogens with pure antagonistic properties, particularly targeting the mammary gland and endometrium to avoid endometrial cancer risks.

Our research has led to the synthesis of EM-652 (SCH 57068) and its precursor EM-800 (SCH57050), which are potent non-steroidal antiestrogens. EM-652 exhibits the highest binding affinity to the estrogen receptor, surpassing estradiol and other competitors like ICI 182780 and hydroxytamoxifen. It is notably effective against both ER alpha and ER beta, and unlike hydroxytamoxifen, it inhibits both AF1 and AF2 functions of these receptors, which are crucial for growth factor and oncogene activity.

EM-652's capacity to inhibit ligand-independent AF1 activation, which is linked to receptor phosphorylation by kinases, is a key feature. It also suppresses Ras-induced transcriptional activity and blocks the action of SRC-1, a coactivator of the receptors. The pure antiestrogen EM-652 nullifies the SRC-1-induced ER beta activity, unlike hydroxytamoxifen, which does not, highlighting the importance of pure antiestrogens in breast cancer treatment.

EM-800 has been shown to prevent mammary carcinoma in rats, a model akin to human breast cancer. The addition of dehydroepiandrosterone to EM-800 resulted in complete tumor inhibition. Furthermore, EM-800 treatment reduced uterine size and the presence of estrogen receptors in the uterus, vagina, and tumors. EM-652 demonstrated the most potent inhibition of human breast cancer cell growth in vitro, contrasting with the stimulatory effects of hydroxytamoxifen and droloxifene on cell proliferation. It also effectively reduced the percentage of cycling cancer cells.