In vitro activity: LXR623 (formerly known as WAY-252623) is a clinically viable, highly brain-penetrant, highly selective and orally bioavailable synthetic modulator of LXR (Liver X receptor). As a LXRα-partial/LXRβ-full agonist, LXR623 selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. LXR623 displayed high efficacy in reducing lesion progression in the murine LDLR(-/-) atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters. LXR-623 potently kills U87EGFRvIII and GBM39 cells in vitro while completely sparing NHAs. LXR-623 also increases ABCA1 protein and decreases LDLR protein levels in all three cell lines.

Kinase Assay: LXR-623 is a brain-penetrant partial LXRα and full LXRβ agonist, with IC50s of 24 nM and 179 nM, respectively.

Cell Assay: LXR-623 treatment of human PBMC in vitro significantly increases transcription of ABCA1 and ABCG1. LXR-623 potently kills U87EGFRvIII and GBM39 cells in vitro while completely sparing NHAs. LXR-623 also increases ABCA1 protein and decreases LDLR protein levels in all three cell lines. LXR-623 suppresses LDLR expression, increases expression of the ABCA1 efflux transporter, and induces substantial cell death in all of the GBM samples tested. LXR-623 (5 μM) also induces GBM cell death through activation of LXRβ.