DO-264

DO-264 is a selective and in vivo-active inhibitor of Abhydrolase Domain Containing 12 (ABHD12), with an IC₅₀ of 11 nM. IC50 & Target: IC50: 11 nM (ABHD12)^[1]. In Vitro: DO-264 displays an IC₅₀ value of 11 nM (9.6 nM-13 nM). DO-264 blocks lyso-PS hydrolysis activities of recombinant mouse and human ABHD12 in transfected HEK293T cell lysates (DO-264 IC₅₀ values of ~30 and 90 nM against mouse and human ABHD12, respectively) and the ABHD12-dependent lyso-PS lipase activity of membrane lysates from mouse brain (IC₅₀=2.8 nM, 2.4 nM-3.3 nM) and human THP-1 cells (IC₅₀= 8.6 nM, 6.3 nM-12 nM)^[1]. In Vivo: Mice treated with DO-264 display dose-dependent increases in brain lyso-PS and 20:4 PS content that are qualitatively similar to the changes observed in ABHD12^–/– mice. DO-264-treated mice, however, show minimal impairment in auditory function following four weeks of drug exposure. Both ABHD12^–/– and DO-264-treated mice display exacerbated immunopathology following infection with the lymphocytic choriomeningitis virus (LCMV) clone 13, resulting in severe inflammatory lung damage, heightened chemokine production, and, in some cases, death^[1].