Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis.

雌激素相关受体（ERR）是能量稳态的关键调节因子，在代谢紊乱、骨骼肌相关疾病和神经退行性疾病的病因学中发挥着重要作用。在三种 ERR 亚型中，ERRα 成为代谢和神经退行性疾病的潜在药物靶点。尽管已经鉴定了 ERRβ/γ 选择性激动剂化学工具，但还没有有效靶向 ERRα 激动剂的化学工具。我们成功地将高亲和力 ERRα 激动剂设计成具有选择性 ERRβ/γ 激动剂活性的化学支架 ( GSK4716 )，提供了新型 ERRα/β/γ 泛激动剂，可用作探测这些核受体生理作用的工具。我们确定了增强 ERRα 选择性的结构要求。分子模型表明，我们的新型调节剂在 ERRα 的 LBP 中具有有利的结合模式，并且可以诱导构象变化，其中最初占据口袋的 Phe328 发生脱位，以将配体容纳在相当小的空腔中。最好的激动剂上调靶基因 PGC-1α 和 PGC-1β 的表达，这是实现最大线粒体生物合成所必需的。此外，它们还增加了 PDK4 的 mRNA 水平，而 PDK4 在能量稳态中发挥着重要作用。