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

Area of Science:

• Endocrinology
• Oncology
• Medicinal Chemistry

Background:

• Endocrine resistance to tamoxifen and aromatase inhibitors affects up to 50% of ER+ breast cancer patients.
• This resistance often leads to an endocrine-independent ER+ phenotype, necessitating alternative treatment strategies.
• Selective ER downregulators (SERDs) can ablate ER, potentially targeting both endocrine-dependent and -independent ER+ tumors.

Purpose of the Study:

• To design and optimize novel selective estrogen receptor downregulators (SERDs) based on the 6-OH-benzothiophene (BT) scaffold.
• To evaluate the in vitro and in vivo efficacy of these novel BT SERDs against treatment-resistant ER+ breast cancer models.
• To compare the efficacy of novel BT SERDs with existing agents like GDC-0810/ARN-810.

Main Methods:

• Optimization of novel BT SERDs using treatment-resistant (TR) ER+ cell lines (MCF-7:5C, MCF-7:TAM1).
• Validation in parent endocrine-dependent cell line (MCF-7:WS8) using 2D and 3D cultures.
• Assays included ERα in-cell westerns, ERE-luciferase, and cell viability assays.

Main Results:

• Two novel BT SERDs demonstrated superior in vitro activity compared to GDC-0810/ARN-810.
• These compounds exhibited favorable bioavailability in preclinical studies.
• The novel BT SERDs significantly regressed treatment-resistant, endocrine-independent ER+ xenografts, outperforming GDC-0810/ARN-810.

Conclusions:

• Novel 6-OH-benzothiophene (BT) based SERDs exhibit potent anti-tumor activity against treatment-resistant ER+ breast cancer.
• These compounds show promise as superior alternatives to existing SERDs, addressing limitations of current therapies.
• Further development of these BT SERDs could offer a new therapeutic strategy for endocrine-resistant breast cancer.