Galunisertib

Galunisertib is a potent, selective, and orally bioavailable inhibitor of transforming growth factor-beta receptor type I (TGF-βRI) kinase. It blocks TGF-β-induced signaling by inhibiting Smad2 phosphorylation, a key step in the TGF-β/Smad pathway. Galunisertib exhibits an IC₅₀ of 56 nM in cell-free assays.

Key features and applications include:

• Selective TGF-βRI Inhibition: Specifically targets ALK5 (TGF-βRI), minimizing off-target effects on other kinases.
• Smad2 Pathway Blockade: Inhibits TGF-β-induced Smad2 phosphorylation, reducing transcription of pro-fibrotic and pro-tumorigenic genes.
• Cancer Stem Cell Modulation: Shown to inhibit self-renewal and survival of cancer stem-like cells.
• Orally Active: Suitable for in vivo studies and clinical development.

Research Applications:

• Tumor microenvironment and immune evasion studies
• Fibrosis and epithelial-to-mesenchymal transition (EMT) models
• Cancer stem cell biology
• Combination therapy with immune checkpoint inhibitors or chemotherapy

Relevant disease states include:

• Cancer: Investigated in clinical trials for hepatocellular carcinoma, glioblastoma, pancreatic, and colorectal cancers due to its ability to suppress tumor growth and metastasis.
• Fibrotic Diseases: Explored in models of liver, lung, and kidney fibrosis where TGF-β signaling drives pathological tissue remodeling.
• Immuno-Oncology: Enhances anti-tumor immunity by reducing TGF-β-mediated immunosuppression in the tumor microenvironment.