XL041

XL041 (BMS-852927) is an LXRβ-selective agonist. IC50 & Target: LXRβ^[1] In Vitro: XL041 (BMS-852927) is an LXRβ-selective agonist with 20% LXRα and 88% LXRβ activity compared to a full pan agonist in transactivation assays. XL041 is potent, with an EC₅₀=9 nM and 26% activity in an in vitro human whole-blood endogenous target gene activation assay (WBA). BMS-852927 has similar binding affinity to LXRα and LXRβ (19 and 12 nM, respectively)^[1]. In Vivo: XL041 (BMS-852927), has a very favorable profile at efficacious doses in cynomolgus monkeys and mice. XL041 pre-treatment of C57BL/6J mice for 7 days results in potent, dose-dependent stimulation of cholesterol efflux in this system, reaching a maximum in the 3 mg/kg/day dose group of 70% above vehicle in the initial efflux rate. Similar results are obtained in LDLR knockout (KO) mice. In a separate study, XL041 inhibits the progression of atherosclerosis in a 12 week study in LDLR KO mice. Importantly, the dose response for inhibition of atherosclerosis (0.1-3 mg/kg/day) is similar to the dose response for macrophage reverse cholesterol transport (RCT) stimulation (0.03-3 mg/kg/day), a major underlying mechanism through which LXR agonists affect the disease^[1].