tamoxifen and benzothiophene

Endocrine therapy (ET) has benefited patients with estrogen receptor alpha (ERα) positive breast cancer for decades. Selective estrogen receptor modulator (SERM) such as Tamoxifen represents the clinical standard of care (SoC). Despite the therapeutic importance of current SoC agents, 30-50% of prolonged treatment patients inevitably generated resistant tumor cells, usually eventually suffered tumor relapse and developed into metastatic breast cancer (MBC), which was the leading cause of female cancer-related mortality. Among these, most resistant tumors remained dependent on ERα signaling, which reignited the need for the next generation of ERα related agents. We hypothesized that selective estrogen receptor covalent antagonists targeting ERα would provide a therapeutic alternative. In the current work, series of novel benzothiophene hybrids bearing electrophile moieties were synthesized and biologically evaluated. The representative analogue 15c exhibited potent anti-proliferative effect in MCF-7 cell lines in vitro, and further mechanism studies confirmed the necessity of covalent bonding. More importantly, 15c could attenuate the expression of TFF-1, GREB-1 and downregulate the levels of cellular ERα protein.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Estrogen Receptor Antagonists; Female; Humans; MCF-7 Cells; Molecular Structure; Receptors, Estrogen; Structure-Activity Relationship; Thiophenes; Tumor Cells, Cultured

Estrogen receptor α emerged as a well validated therapeutic target of breast cancer for decades. However, approximately 50% of patients who initially responding to standard-of-care (SoC), such as undergo therapy of Tamoxifen, generally inevitably progress to an endocrine-resistance ER+ phenotype. Recently, selective estrogen receptor covalent antagonists (SERCAs) targeted to ERα have been demonstrated as a therapeutic alternative. In the present study, series of novel 6-OH-benzothiophene (BT) derivatives targeting ERα and deriving from Raloxifene were designed, synthesized, and biologically evaluated as covalent antagonists. Driven by the antiproliferative efficacy in ER+ breast cancer cells, our chemical optimization finally led to compound 19d that with potent antagonistic activity in ER+ tumor cells while without agonistic activity in endometrial cells. Moreover, the docking simulation was carried out to elucidate the binding mode, revealing 19d as an antagonist and covalently binding to the cysteine residue at the 530 position of ER helix H11.

Topics: Dose-Response Relationship, Drug; Drug Design; Estrogen Antagonists; Estrogen Receptor alpha; Humans; Molecular Structure; Structure-Activity Relationship; Thiophenes

The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing

Topics: Animals; Apoptosis; Aromatase Inhibitors; Breast Neoplasms; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Mutation; Proteolysis; Rats; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators; Thiophenes; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Resistance to the selective estrogen receptor modulator tamoxifen and to aromatase inhibitors that lower circulating estradiol occurs in up to 50% of patients, generally leading to an endocrine-independent ER+ phenotype. Selective ER downregulators (SERDs) are able to ablate ER and thus, theoretically, to prevent survival of both endocrine-dependent and -independent ER+ tumors. The clinical SERD fulvestrant is hampered by intramuscular administration and undesirable pharmacokinetics. Novel SERDs were designed using the 6-OH-benzothiophene (BT) scaffold common to arzoxifene and raloxifene. Treatment-resistant (TR) ER+ cell lines (MCF-7:5C and MCF-7:TAM1) were used for optimization, followed by validation in the parent endocrine-dependent cell line (MCF-7:WS8), in 2D and 3D cultures, using ERα in-cell westerns, ERE-luciferase, and cell viability assays, with 2 (GDC-0810/ARN-810) used for comparison. Two BT SERDs with superior in vitro activity to 2 were studied for bioavailability and shown to cause regression of a TR, endocrine-independent ER+ xenograft superior to that with 2.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Mice, Nude; Models, Molecular; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Thiophenes