Inhibiting Endothelial Cell Function in Normal and Tumor Angiogenesis Using BMP Type I Receptor Macrocyclic Kinase Inhibitors

Angiogenesis, i.e., the formation of new blood vessels from pre-existing endothelial cell (EC)-lined vessels, is critical for tissue development and also contributes to neovascularization-related diseases, such as cancer. Vascular growth factor (VEGF) bone morphogenetic proteins (BMPs) are among many secreted cytokines that regulate EC function. While several pharmacological anti-angiogenic agents have reached clinic, further improvement needed increase clinical efficacy overcome acquired therapy resistance. More insights into functional consequences targeting specific pathways modulate vessel may lead therapeutic approaches. Here, we synthesized identified two macrocyclic small molecular compounds termed OD16 OD29 inhibit BMP type I receptor (BMPRI)-induced SMAD1/5 phosphorylation downstream gene expression in ECs. Of note, demonstrated higher specificity against BMPRI activin receptor-like kinase 1/2 (ALK1/2) than commonly used molecule inhibitor LDN-193189. OD29, but not OD16, potently inhibited VEGF-induced extracellular regulated MAP In vitro, exerted strong inhibition BMP9 ECs migration, invasion cord formation. Using Tg (fli:EGFP) zebrafish embryos, found antagonized dorsal longitudinal anastomotic (DLAV), intra segmental (ISV), subintestinal (SIV) during embryonic development. Moreover, MDA-MB-231 breast cancer cell-induced tumor angiogenesis embryos was significantly decreased by OD29. Both might provide a steppingstone novel anti-angiogenesis agents.