Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer

Area of Science:

• Oncology
• Pharmacology
• Medicinal Chemistry

Background:

• Fulvestrant, a steroidal selective estrogen receptor degrader (SERD), is effective for metastatic breast cancer but has poor pharmacokinetics.
• Development of orally bioavailable, nonsteroidal SERDs is ongoing, but brain metastases are often excluded due to poor blood-brain barrier penetration.

Purpose of the Study:

• To synthesize and evaluate a novel family of benzothiophene-based SERDs (B-SERDs) with oral and brain bioavailability.
• To assess the efficacy of these B-SERDs in preclinical models, including those resistant to endocrine therapy or with ESR1 mutations.

Main Methods:

• Synthesis of a novel family of benzothiophene SERDs with a basic amino side arm.
• Evaluation of ERα degradation, binding affinity, and in vitro potency and efficacy.
• Testing of a lead compound (37d) in an orthotopic xenograft model of endocrine-resistant ER+ breast cancer.

Main Results:

• B-SERDs successfully induced proteasomal degradation of ERα.
• These compounds demonstrated oral and brain bioavailability, high affinity binding to ERα, and comparable potency/efficacy to fulvestrant in resistant cell lines.
• Compound 37d, featuring a 3-oxyazetidine side chain, caused regression of endocrine-resistant ER+ tumors in a mouse model.

Conclusions:

• Novel B-SERDs offer potential for improved treatment of metastatic breast cancer, including brain metastases.
• Compound 37d represents a promising candidate for further development against endocrine-resistant and ESR1-mutated breast cancers.