Natural product and natural product-like molecules continue to be important for the development of pharmaceutical agents, as molecules in this class play a vital role in the pipeline for new therapeutics. Among these, tetracyclic terpenoids are privileged, with >100 being FDA-approved drugs. Despite this significant pharmaceutical success, there remain considerable limitations to broad medicinal exploitation of the class due to lingering scientific challenges associated with compound availability. Here, we report a concise asymmetric route to forging natural and unnatural (enantiomeric) C19 and C20 tetracyclic terpenoid skeletons suitable to drive medicinal exploration. While efforts have been focused on establishing the chemical science, early investigations reveal that the emerging chemical technology can deliver compositions of matter that are potent and selective agonists of the estrogen receptor beta, and that are selectively cytotoxic in two different glioblastoma cell lines (U251 and U87).
The estrogen related receptors (ERRs) are a subgroup of nuclear receptors that play a role in regulation of cellular metabolism. Prostate cancer (PCa) cells display altered metabolic signatures, such as the Warburg effect, and the ERRs have been implicated in driving this phenotype. Despite the lack of a known endogenous ligand, synthetic ligands that target the ERRs have been discovered. For example, the ERRα inverse agonist XCT790 modulates metabolic pathways in PCa cells, but it also functions as a mitochondrial uncoupler independent of targeting ERRα. Here, we describe a novel dual ERRα/γ inverse agonist, SLU-PP-1072, derived from the GSK4716 ERRγ agonist scaffold that is distinct from the XCT790 scaffold. SLU-PP-1072 alters PCa cell metabolism and gene expression, resulting in cell cycle dysregulation and increased apoptosis without acute mitochondrial uncoupling activity. Our data suggest that inhibition of ERRα/γ may be beneficial in treatment of PCa, and SLU-PP-1072 provides a unique chemical tool to evaluate the pharmacology of ERRα and ERRγ.
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