XL041 (BMS-852927) is an agonist selective for LXRβ.

XL041 (BMS-852927) functions as an LXRβ-selective agonist, exhibiting 20% activity towards LXRα and 88% towards LXRβ relative to a comprehensive pan agonist in transactivation assays. Despite similar binding affinities to LXRα and LXRβ (19 and 12 nM, respectively)[1], XL041 proves to be potent, with an EC50 of 9 nM and achieves 26% activity in an in vitro human whole-blood endogenous target gene activation assay (WBA).

XL041 (BMS-852927) exhibits a highly favorable efficacy profile at therapeutic doses in both cynomolgus monkeys and mice. In a distinct study, the compound effectively inhibited the progression of atherosclerosis over a 12-week period in LDLR knockout (KO) mice. Additionally, pre-treating C57BL/6J mice with XL041 for seven days induced a potent and dose-dependent increase in cholesterol efflux, peaking at a 70% enhancement over the control with a dose of 3 mg/kg/day. This effect was also observed in LDLR KO mice. Notably, the dosage range that inhibits atherosclerosis (0.1-3 mg/kg/day) aligns closely with the dosage range that stimulates macrophage reverse cholesterol transport (RCT) (0.03-3 mg/kg/day), indicating a conserved mechanism of action for LXR agonists in mitigating the disease.