Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Endocrine resistance is a major challenge in treating estrogen receptor alpha-positive (ERα+) breast cancer (BC).
• Existing therapies often face limitations due to resistance mechanisms.
• Targeting ERα degradation and microtubule dynamics offers a potential therapeutic strategy.

Purpose of the Study:

• To develop novel dual-functional compounds with ERα degradation and tubulin depolymerization capabilities.
• To evaluate the efficacy of these compounds against ERα+ breast cancer, including endocrine-resistant models.
• To provide a basis for new dual-target drug development for breast cancer therapy.

Main Methods:

• Synthesis of novel bridged bicyclic compounds with selenocyano (SeCN) side chains.
• Assessment of ERα degradation and tubulin depolymerization activity in vitro.
• Evaluation of antiproliferative effects in ERα+ BC cell lines (wild-type and mutant ERα).
• In vivo studies using MCF-7 and LCC2 xenograft models.

Main Results:

• Compounds 35s and 35t demonstrated potent ERα degradation and tubulin depolymerization.
• These compounds exhibited significant antiproliferative activity in various ERα+ BC cell lines.
• Compound 35t induced G2/M phase cell cycle arrest by disrupting the microtubule network.
• In vivo, 35s and 35t effectively suppressed tumor growth in xenograft models with minimal toxicity.

Conclusions:

• Novel dual-functional ERα degraders with selenocyano side chains are effective against ERα+ breast cancer.
• These compounds target both ERα and tubulin, offering a promising strategy for overcoming endocrine resistance.
• Compounds 35s and 35t represent potential drug candidates for treating resistant breast cancer variants.