Abstract 1282: IND-enabling characterization of the selective GPER agonist, LNS8801
| Autor: | Chris Natale, Tina Garyantes |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Cancer Research. 81:1282-1282 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2021-1282 |
| Popis: | 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 dog1000 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. |
| Databáze: | OpenAIRE |
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