Bazedoxifene and Beyond: Identifying This SERM's Targets and Deciphering Its Molecular Mechanisms

Area of Science:

• Pharmacology and Drug Discovery
• Molecular Biology
• Oncology

Background:

• Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), is approved for osteoporosis treatment.
• BZA exhibits in vitro off-target interactions beyond estrogen receptors, suggesting potential for drug repurposing and novel therapeutic applications.
• Understanding these off-target effects is crucial for exploring new uses and potential side effects.

Purpose of the Study:

• To comprehensively review established and newly identified molecular targets of BZA beyond estrogen receptors.
• To elucidate the molecular mechanisms underlying BZA's interactions with various cellular targets.
• To identify new avenues for research and potential therapeutic applications of BZA.

Main Methods:

• Systematic literature review of over 1500 articles.
• Selection of key studies investigating BZA targets and mechanisms.
• Analysis of evidence from computational studies, direct interaction assays, and functional testing.

Main Results:

• Detailed examination of BZA's role in estrogen receptor signaling and interactions with glycoprotein 130.
• Compilation of potential BZA interactions with cannabinoid receptors, biotransformation pathways, DNA cycle, Sars-CoV-2, ferroptosis, ROS production, and cholesterol biosynthesis.
• Evidence supporting BZA's diverse molecular interactions across multiple signaling pathways.

Conclusions:

• This review provides the most complete overview of BZA's molecular mechanisms to date.
• BZA's off-target interactions offer significant potential for drug repurposing in various therapeutic areas, including cancer research.
• Further research into these novel targets can unlock new applications for BZA beyond osteoporosis treatment.