GI 254023X

GI 254023X is an inhibitor of the metalloproteinase-disintegrin ADAM10 (IC₅₀ = 5.3 nM).¹ It is selective for ADAM10 over ADAM17, matrix metalloproteinase-1 (MMP-1), and MMP-3 (IC₅₀s = 541, 108, and 187 nM, respectively), but also inhibits MMP-9 and MMP-13 (IC₅₀s = 2.5 and 1.1 nM, respectively). GI 254023X inhibits constitutive shedding of CX3CL1, but not shedding induced by phorbol 12-myristate 13-acetate (PMA; Item No. 10008014), in COS-7 cells transfected with human chemokines (IC₅₀s = 0.4 and >10 μM, respectively). It also inhibits constitutive, but not PMA-induced, secretion of the IL-6 receptor (IL-6R) from THP-1 macrophages (IC₅₀s = 1.8 and >10 μM, respectively). GX 254023X (1 μM) decreases shedding of low density lipoprotein receptor-related protein 1 (LRP1) induced by amyloid-β (1-42) (Aβ42; Item No. 20574) in human brain microvessel endothelial cells (HBMECs) and increases Aβ42 transit across an in vitro blood brain barrier model in a concentration-dependent manner.² In vivo, GI 254023X (200 mg/kg) reduces brain LRP1 shedding and increases plasma levels of Aβ40 in a mouse model of Alzheimer's disease.

WARNING This product is not for human or veterinary use.

1. Ludwig, A., Hundhausen, C., Lambert, M.H., et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb. Chem. High Throughput Screen. 8(2), 161-171 (2005).

2. Shackleton, B., Crawford, F., and Bachmeier, C. Inhibition of ADAM10 promotes the clearance of Aβ across the BBB by reducing LRP1 ectodomain shedding. Fluids Barriers CNS 13(1), 14 (2016).