生物活性

• 描述Transforming growth factor β (TGF-β) type I receptor (ALK5) is a transmembrane serine/threonine kinase. ALK5 forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. Thus, ALK5 participates in regulation of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. GW788388 is an ALK5 kinase inhibitor with IC₅₀ of 18 nM^[3]. NMuMG and MDA-MB-231 cells were treated with GW788388 at the concentrations of 1 μM, 5 μM and 10 μM or 2.5 μM, 5 μM and 10 μM, respectively，in the presence of TGF-β for 1 h and the results showed that GW788388 inhibited TGF-β induced Smad2 phosphorylation in a dose-dependent manner in both cell lines^[4]. In a rat model of chemically induced renal fibrosis, GW788388 administration at the doses of 3 mg/kg or 10 mg/kg u.i.d. significantly decreased relative collagen IA1 mRNA levels^[3]. In a renal fibrosis model using db/db mice, GW788388 given orally at the dose of 2 mg/kg/day for 5 weeks significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys^[4]. In a mouse model of bleomycin-induced dermal fibrosis, GW788388 given i.p. at the dose of 2 mg/kg/day prevented the fibrotic response^[5].
• 作用机制GW788388 is an ATP competitive inhibitor of the kinase domain of ALK5^[4].