Chemical optimization of the exercise mimetic SLU-PP-332 enables insight into estrogen-related receptor signaling.
This study presents the first comprehensive structure-activity relationship (SAR) analysis of SLU-PP-332, a synthetic agonist of estrogen-related receptors (ERRα and ERRγ) — nuclear receptors that regulate mitochondrial metabolism and exercise-responsive gene transcription. The researchers synthesized a library of SLU-PP-332 analogues and systematically varied core pharmacophoric elements, evaluating their effects using cell-based functional assays, downstream gene-expression profiling, and computational modeling (docking and molecular dynamics simulations). The study found that specific structural features of the SLU-PP-332 scaffold govern ERR potency, transcriptional efficacy, selectivity, ligand efficiency, solubility, and metabolic stability. While SLU-PP-332 remained a strong benchmark, certain analogues showed comparable or context-dependent transcriptional activity alongside improvements in ligand efficiency, solubility, or metabolic stability. Computational analyses helped explain how subtle chemical modifications influence receptor engagement and downstream signaling. Limitations include reliance on cell-based and in silico methods with no animal or human data reported. The work establishes design principles for next-generation ERR agonists and positions these compounds as potential exercise-mimetic therapeutics, though extensive preclinical and clinical validation remains to be done.
Why this grade: All experimental findings are derived from cell-based functional assays, gene-expression profiling, and computational modeling with no animal or human studies reported.
Estrogen-related receptors (ERRs) are master regulators of mitochondrial metabolism and exercise-responsive transcription, yet only a limited number of synthetic agonists with suitable potency and drug-like properties have been reported. SLU-PP-332 is a well-established exercise mimetic and widely used chemical probe for ERR activation; however, the structural features governing its potency, efficacy, selectivity, and drug-like properties have not been systematically elucidated. Here, we report the first comprehensive structure-activity relationship (SAR) analysis of the SLU-PP-332 scaffold, integrating chemical synthesis, cell-based functional assays, downstream gene-expression profiling, and computational modeling. Through iterative modification of core pharmacophoric elements, we identify key structural determinants that control ERRα and ERRγ agonism, transcriptional efficacy, ligand efficiency, and physicochemical properties. While SLU-PP-332 remains a strong benchmark for ERR activation, several analogues achieve comparable or context-dependent transcriptional responses while exhibiting improved ligand efficiency, solubility, or metabolic stability. Computational docking and molecular dynamics simulations reveal how subtle structural modifications influence ERR engagement and signaling outcomes. Together, this work defines design principles for tuning ERR agonism and provides a foundational SAR roadmap for the rational development of next-generation ERR agonists and exercise-mimetic therapeutics.
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