A novel steroidal inhibitor of estrogen-related receptor alpha (ERR alpha)

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Estrogen-related receptor alpha (ERRalpha) is implicated in human malignancies like breast, prostate, and colon cancer.
• ERRalpha regulates cellular energy metabolism via co-activator proteins (e.g., PGC-1alpha), influencing genes in mitochondrial biogenesis and fatty acid oxidation.
• Targeting ERRalpha offers a novel therapeutic approach for solid tumors, particularly by addressing tumor cell energy metabolism under stress.

Purpose of the Study:

• To describe a novel steroidal antiestrogen, SR16388, with selective binding to ERRalpha.
• To evaluate the efficacy of SR16388 as a potential antitumor agent and chemical probe for ERRalpha biology.

Main Methods:

• Selective binding of SR16388 to ERRalpha was confirmed using time-resolved fluorescence resonance energy transfer (TR-FRET) assays.
• Reporter gene assays assessed SR16388's inhibition of ERRalpha transcriptional activity and co-activator recruitment.
• In vivo studies involved human prostate tumor xenografts in nude mice, evaluating SR16388 as a single agent and in combination with paclitaxel.
• In vitro studies assessed SR16388's effect on diverse human tumor cell line proliferation.

Main Results:

• SR16388 selectively binds to ERRalpha, inhibiting its transcriptional activity and preventing co-activator (PGC-1alpha/ERRalpha) recruitment.
• SR16388 demonstrated significant inhibition of human prostate tumor xenograft growth in vivo, both as a single agent and in combination with paclitaxel.
• SR16388 effectively inhibited the proliferation of various human tumor cell lines in vitro.

Conclusions:

• SR16388 is a potent and selective ERRalpha inhibitor with demonstrated antitumor activity.
• SR16388 shows promise as an experimental antitumor agent for solid tumors.
• SR16388 serves as a valuable chemical probe for investigating ERRalpha biology and its role in cancer metabolism.