PD 173074

PD 173074 (CAS No. 219580-11-7) is a highly selective tyrosine kinase inhibitor. Its core biological function is to inhibit fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) activity, blocking angiogenesis, tumor cell proliferation, and metastasis mediated by related signaling pathways. It can also reverse ABCB1/ABCC10-mediated multidrug resistance, and in schizophrenia-related studies it has shown potential for high-affinity binding to FGFR1. Its targets and mode of action are inhibition of the tyrosine kinase activity of FGFR1 (primary target), FGFR3, and VEGFR2 (ATP-competitive binding to the ATP-binding pocket of FGFR1), antagonizing FGF-2-mediated biological effects, with low selectivity toward other kinases such as PDGFR, c-Src, EGFR, and the insulin receptor.

Key activity data: FGFR1 binding IC₅₀ 21.5±0.8 nM, functional cAMP IC₅₀ 15.7±5.4 nM; mouse FGFR1 IC₅₀ 122 nM, rat 727±350 nM, rhesus monkey 55.5 nM; VEGFR2 autophosphorylation inhibition IC₅₀ 100-200 nM; PDGFR IC₅₀ 17.6±1.9 μM, c-Src IC₅₀ 19.8±2.3 μM; EGFR and insulin receptor IC₅₀ both > 50 μM.

Animal modeling is commonly used for model treatment; common models include the mouse corneal neovascularization model (to evaluate inhibition of FGF/VEGF-induced angiogenesis), the human GCGR transgenic mouse acute glucagon challenge model, colorectal cancer xenograft models, head and neck squamous cell carcinoma (HNSCC)-related models, and schizophrenia-related models.

Common applications and concentrations: In cell culture, CHO-hGCGR cells use nM-level concentrations for receptor binding and functional assays; HNSCC cell lines (e.g., A253, CAL-27, etc.) are used for drug sensitivity testing; ABCB1-overexpressing cell lines (e.g., HEK293, human epidermoid carcinoma drug-resistant sublines) use 100 μM-level concentrations for multidrug resistance reversal experiments. In animal studies, intraperitoneal injection in mice at 1-2 mg/kg/d is used to inhibit corneal neovascularization, and oral dosing at 3-30 mg/kg is used for treatment in tumor-related models. Effective treatment concentrations: in animal studies, 1 mg/kg/d can inhibit 86% of FGF-induced angiogenesis and 2 mg/kg/d can inhibit 81% of VEGF-induced angiogenesis; at the cellular level, nM-level concentrations can significantly inhibit FGFR1/VEGFR2 activity, and 100 μM-level concentrations can reverse ABCB1-mediated paclitaxel and vinblastine resistance. In HNSCC cells, the methylation status of specific CpG sites is associated with drug sensitivity, and hypomethylated cells are more sensitive to it.

References:

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