Development of improved SRC-3 inhibitors as breast cancer therapeutic agents

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Steroid receptor coactivators (SRCs) play critical roles in cancer initiation and progression.
• SRCs enhance transcription of genes involved in cancer cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition (EMT).
• Targeting SRCs with small molecule inhibitors (SMIs) is a potential strategy for cancer therapy.

Purpose of the Study:

• To identify and develop novel SRC SMIs for cancer treatment.
• To evaluate the efficacy of SI-2 analogs, SI-10 and SI-12, in preclinical cancer models.
• To assess the therapeutic potential of SI-10 and SI-12 in inhibiting breast cancer progression and metastasis.

Main Methods:

• High-throughput screening identified SI-2 as a potent SRC SMI.
• SI-2 analogs, SI-10 and SI-12, were synthesized with fluorine atom modifications.
• In vitro assays assessed cell viability, migration, and invasion.
• In vivo studies utilized patient-derived xenograft (PDX) organoids, xenograft tumor models, and spontaneous/experimental metastasis models in mice.

Main Results:

• SI-10 and SI-12 demonstrated prolonged plasma half-life, minimal toxicity, and improved hERG activity compared to SI-2.
• Low nanomolar concentrations of SI-10 and SI-12 inhibited breast cancer cell viability, migration, and invasion in vitro.
• SI-10 and SI-12 repressed the growth of breast cancer PDX organoids and xenograft tumors.
• Both compounds effectively inhibited lung metastasis in spontaneous and experimental metastasis mouse models.

Conclusions:

• SI-10 and SI-12 are potent SRC SMIs with favorable pharmacokinetic and safety profiles.
• These analogs exhibit significant efficacy in inhibiting breast cancer cell proliferation, invasion, and metastasis.
• SI-10 and SI-12 represent promising therapeutic agents for controlling aggressive breast cancer and preventing metastasis.