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

Abstract

Estrogen effects in tissue are mediated in part through activation of the that LNS8801 suppresses cancer in a GPER-dependent manner and that surface estrogen receptor G protein–coupled estrogen receptor (GPER), a LNS8801 is efficacious when administered orally. Furthermore, we show broadly expressed G protein–coupled receptor that affects a wide range that GPER is widely, but not ubiquitously, expressed in both normal and of normal and pathologic processes, including metabolism, vascular malignant human tissues. In addition, an attenuated response to health, inflammation, and cancer. A commonly used synthetic and LNS8801 is observed in a common germline coding variant in human specific GPER agonist, named G-1, antagonizes tumors by promoting GPER. These findings support ongoing human cancer trials with cellular differentiation and enhancing tumor immunogenicity. G-1 is a LNS8801 and suggest that the germline GPER genotype may serve as a racemic compound, and since its discovery, the question of whether both predictive biomarker of therapeutic response. enantiomers display agonist activity or the agonist activity resides primarily in a single enantiomer has never been fully resolved. Herein, we Significance: GPER is broadly expressed in human tissues and has tumor-disclose the isolation of the pure enantiomers of G-1 and determine that suppressive activity. No FDA-approved agents selectively target GPER. the desirable activity resides exclusively in one enantiomer, named LNS8801 is a synthetic, orally bioavailable, enantiomerically pure, GPER agLNS8801, whose configuration we have unambiguously determined by onist with potent anticancer activity in vivo. LNS8801 response is attenuated single-crystal X-ray structure analysis. Using preclinical models, we show by a common germline coding variant present in roughly half of humans.