Adavivint is a potent and selective inhibitor of canonical Wnt signaling, with an EC50 of 19.5 nM via a high-throughput TCF/LEF-reporter assay in SW480 colon cancer cells.
The Wnt pathway plays an important role in cell differentiation, organogenesis, morphogenesis, and tissue remodeling. Adavivint is a small-molecule Wnt pathway inhibitor with an EC50 value of 19.5nM for the TCF/LEF reporter but had no effect on the SV40 luciferase reporter. Treatment of bone-marrow-derived human mesenchymal stem cells (hMSCs; CD29+, CD44+, CD166+, CD105+, CD45−) with 30nM adavivint resulted in a concentration-dependent decrease in the expression of Wnt pathway genes (ASCL1, LEF1, TCF7L2, TCF7, C-MYC, and AXIN2). Adavivint also dose-dependently promoted the aggregation of hMSCs with an EC50 value of 10nM. Compared to DMSO-treated controls, hMSCs treated with adavivint (30nM) for 3 days showed significantly increased expression of Sox9. Adavivint treatment also downregulated the genes associated with tendon or ligament differentiation (COL1A1) and osteoblast differentiation (osteocalcin, alkaline phosphatase, BMP4, RUNX2) in hMSCs. Treatment of adavivint (30nM) for 21 days induced chondrocyte differentiation in mouse chondrogenic ATDC5 cells. Primary mouse embryo calvarial cells exposed to 100 nM of adavivint for 21 days showed increased number and size of Alcian Blue stained chondrocytes compared with DMSO-treated controls. A single IA injection of adavivint (0.3 μg) promoted cartilage growth, improved joint health, decreased cartilage breakdown, and inhibited the Wnt pathway in a rat model of knee osteoarthritis[1].
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