Abstract 1282: IND-enabling characterization of the selective GPER agonist, LNS8801

Abstract

Abstract LNS8801 is the first-in-class, small molecule, orally bioavailable, agonist of GPER being developed for the treatment of patients with advanced cancer. LNS8801 is highly selective for GPER over the classical nuclear hormone estrogen receptors α and β, and it was also highly selective for GPER in Eurofins' Safety47 panel. LNS8801 has very low aqueous solubility and is highly protein bound. Pharmacokinetic studies demonstrate that LNS8801 has high clearance and moderate, solubility-dependent, oral bioavailability. The rank ordering of metabolic liability in hepatocytes is dog<human<mouse<rat, which is consistent with the observed clearance rates in these species. LNS8801 metabolism, and thus clearance, is slower in dogs. Oral bioavailability is ~80% and dose proportional in human formulations tested in dogs. LNS8801 is primarily metabolized by oxidation followed by phase II conjugation. In vitro metabolism studies indicate that LNS8801 is a potential substrate for several cytochrome P450 enzymes and thus has a low potential for participating in drug-drug interactions (DDIs). Given that maximal efficacy is expected at low exposures (Cmax of ≤5 nM) and that LNS8801 is highly protein bound, it is unlikely that these effects will cause adverse DDIs in humans. In the pivotal 28-day toxicity studies, the no-observed-adverse-effect level (NOAEL) was >1000 mg/kg/day (the maximum feasible dose) in the rat and 30 mg/kg/day in the dog. Exposure was higher in dogs than in rats due to considerable accumulation. In the dog, mortality at doses that gave very high exposures was attributed to myelopoietic hypocellularity of the bone marrow and subsequent lymphoid depletion in associated organs. The primary target organs were identified as bone marrow, lymphoid tissues, and reproductive organs. Exposure at the canine NOAEL was more than 24,000 times the predicted maximally efficacious exposure in humans, and thus LNS8801 is anticipated to be very safe. Citation Format: Chris Natale, Tina Garyantes. IND-enabling characterization of the selective GPER agonist, LNS8801 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1282.