Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer

Abstract

Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2), have demonstrated clinical efficacy in patients with heavily-treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy, but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and, in contrast to E2, ShERPAs did not cause significant uterine growth.

Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer

“…27 The BT scaffold has the advantage of broad knowledge on metabolic and pharmacokinetic properties derived from 5 and 6 , 27, 28, 32–37 and provides highly potent modulation of ER-mediated biological activity. Herein, we have extended the utility of this scaffold to the design and synthesis of novel ER ligands by substituting an acrylate side chain at the BT 3-position and diversifying substituents at the 2-position, yielding potent, orally bioavailable SERDs.…”

“…Exploration of other heterocycles at this position would be a promising approach to modulate the physicochemical and ADMET properties of next generation SERDs. The partial efficacy of some candidate SERDs ( 14d, 14e, 16b & 19 ) and the differential activity in TR versus parent cell lines is a feature common to ShERPAs 27 and other classes of BT-based ER ligands, which will be the focus of future reports.…”

“…In our previous work on selective human ER partial agonists (ShERPAs), 27 we explored the ability of ER to accommodate a range of substituents exploiting the plasticity of helix 11. Similarly, in the candidate SERDs developed herein, we inserted a ketone linker between the BT core and the phenyl group at the 2-position and subsequently explored a variety of 2-phenyl substituents to fine tune the molecular topology and to gain potency in our primary and secondary screens.…”

“…Measured RBA for ERα varied from 9.8% to a maximum of 40.3% for compound 28a , with RBA for 2 measured at 53.4%. A quantitative correlation between RBA and cell-based transcriptional potency is not anticipated, 27 because ligand binding affinity to ER as part of a functional, multi-protein complex at DNA is not expected to be identical to affinity for recombinant ER alone.…”

“…27–29 Herein we report a medicinal chemistry campaign towards development of novel orally bioavailable SERDs based on the benzothiophen-6-ol (BT) core of the SERMs 6 and arzoxifene ( 5 ) 30 . Other reports on use of a BT scaffold by Novartis 21 and Shoda 31 , reported modest potency where data was made available.…”