Design, syntheses and evaluations of novel indole derivatives as orally selective estrogen receptor degraders (SERD)

Area of Science:

• Endocrinology and Cancer Biology
• Medicinal Chemistry
• Pharmacology

Background:

• Estrogen receptor-positive (ER+) breast cancer relies on the ER signaling pathway for development.
• Fulvestrant, a current selective estrogen receptor degrader (SERD), is clinically effective but administered via intramuscular injection due to limited bioavailability.

Purpose of the Study:

• To discover and characterize novel indole-based compounds with potent ER degradation capabilities.
• To evaluate the potential of these compounds as orally bioavailable SERDs for ER+ breast cancer treatment.

Main Methods:

• Synthesis and in vitro evaluation of a novel indole series for ER degradation potency.
• Assessment of oral bioavailability and systemic exposure of selected compounds.
• In vivo efficacy studies in an ER+ MCF7 breast cancer cell-derived xenograft (CDX) model following oral administration.

Main Results:

• Identified novel indole compounds exhibiting nanomolar ER degradation potency.
• Demonstrated favorable oral systemic exposure for selected compounds.
• Observed significant suppression of tumor growth in vivo in an ER+ breast cancer model after oral administration.

Conclusions:

• The novel indole series represents a promising class of orally bioavailable SERDs.
• These findings support further optimization towards a preclinical candidate for ER+ breast cancer therapy.