LNS8801: An Enantiomerically Pure Agonist of the G Protein-Coupled Estrogen Receptor Suitable for Clinical Development.

abstractEstrogen effects in tissue are mediated in part through activation of the surface estrogen receptor G protein–coupled estrogen receptor (GPER), a broadly expressed G protein–coupled receptor that affects a wide range of normal and pathologic processes, including metabolism, vascular health, inflammation, and cancer. A commonly used synthetic and specific GPER agonist, named G-1, antagonizes tumors by promoting cellular differentiation and enhancing tumor immunogenicity. G-1 is a racemic compound, and since its discovery, the question of whether both enantiomers display agonist activity or the agonist activity resides primarily in a single enantiomer has never been fully resolved. Herein, we disclose the isolation of the pure enantiomers of G-1 and determine that the desirable activity resides exclusively in one enantiomer, named LNS8801, whose configuration we have unambiguously determined by single-crystal X-ray structure analysis. Using preclinical models, we show that LNS8801 suppresses cancer in a GPER-dependent manner and that LNS8801 is efficacious when administered orally. Furthermore, we show that GPER is widely, but not ubiquitously, expressed in both normal and malignant human tissues. In addition, an attenuated response to LNS8801 is observed in a common germline coding variant in human GPER. These findings support ongoing human cancer trials with LNS8801 and suggest that the germline GPER genotype may serve as a predictive biomarker of therapeutic response. SIGNIFICANCE: GPER is broadly expressed in human tissues and has tumor-suppressive activity. No FDA-approved agents selectively target GPER. LNS8801 is a synthetic, orally bioavailable, enantiomerically pure, GPER agonist with potent anticancer activity in vivo. LNS8801 response is attenuated by a common germline coding variant present in roughly half of humans.