A Synthetic ERR Agonist Alleviates Metabolic Syndrome.

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, ß, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.

Synthesis and structure activity relationship of the first class of LXR inverse agonists.

Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant role in lipid and cholesterol metabolism. Moreover, they are key regulators of several inflammatory pathways. Pharmacological modulation of LXRs holds great potential in treatment of metabolic diseases, neurodegenerative diseases, and cancer. We were the first group to identify LXR inverse agonists SR9238 (6) and SR9243 (7) and demonstrate their potential utility in treating liver diseases and cancer. Here, we present the results of structure-activity relationship (SAR) studies, based around SR9238 (6) and SR9243 (7). This study led to identification of 16, 17, 19, and 38, which were more potent inverse agonists than SR9238 (6) and SR9243 (7) and inhibited expression of the fatty acid synthase gene in DU145 cells. We previously demonstrated that inhibition of FASN is correlated to the anticancer activity of SR9243 (7) and this suggests that new inverse agonists have great potential as anticancer agents. We identified compounds with distinct selectivity toward both LXR isoforms, which can be excellent tools to study the pharmacology of both isoforms. We employed molecular dynamic (MD) simulations to better understand the molecular mechanism underlying inverse agonist activity and to guide our future design.

Development and pharmacological evaluation of a new chemical series of potent pan-ERR agonists, identification of SLU-PP-915.

Estrogen-related receptors (ERR) are an orphan nuclear receptor sub-family that play a critical role in regulating gene transcription for several physiological processes including mitochondrial function, cellular energy utilization and homeostasis. They have also been implicated to play a role in several pathological conditions. Herein, we report the identification, synthesis, structure-activity relationships and pharmacological evaluation of a new chemical series of potent pan-ERR agonists. This template was designed for ERRγ starting from the known acyl hydrazide template and compounds such as agonist GSK-4716 employing a structure-based drug design approach. This led to the preparation of a series of 2,5-disubstituted thiophenes from which several were found to be potent agonists of ERRγ in cell-based co-transfection assays. Additionally, direct binding to ERRγ was established through 1H NMR protein-ligand binding experiments. Compound optimization revealed that the phenolic or aniline groups could be replaced with a boronic acid moiety, which was able to maintain activity and demonstrated improved metabolic stability in microsomal in vitro assays. Further pharmacological evaluation of these compounds showed that they had roughly equivalent agonist activity on ERR isoforms α and ß representing an ERR pan-agonist profile. One potent agonist, SLU-PP-915 (10s), which contained a boronic acid moiety was profiled in gene expression assays and found to significantly upregulate the expression of ERR target genes such as peroxisome-proliferator activated receptor γ co-activators-1α, lactate dehydrogenase A, DNA damage inducible transcript 4 and pyruvate dehydrogenase kinase 4 both in vitro and in vivo.

A Selective ERRα/γ Inverse Agonist, SLU-PP-1072, Inhibits the Warburg Effect and Induces Apoptosis in Prostate Cancer Cells.

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.

A synthesis strategy for tetracyclic terpenoids leads to agonists of ERß.

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).