LDN193189 Tetrahydrochloride

LDN193189 inhibits BMP4-mediated Smad1, Smad5 and Smad8 activation with greater potency than did dorsomorphin (IC ₅₀ =5 nM versus 470 nM) while retaining 200-fold selectivity for BMP signaling versus TGF-β signaling (IC ₅₀ for TGF-β ≥1,000 nM). LDN193189 efficiently inhibits transcriptional activity of the BMP type I receptors ALK2 and ALK3 (IC ₅₀ =5 nM and 30 nM, respectively), and the TGF-β type I receptors ALK4, ALK5 and ALK7 (IC ₅₀ ≥500 nM) and increases selectivity for BMP signaling versus AMP-activated protein kinase, PDGFR and MAPK signaling pathways as compared to the parent compound. LDN193189 blocks the transcriptional activity induced by either constitutively active ALK2 ^R206H or ALK2 ^Q207D mutant proteins. These findings suggest that LDN193189 might affect BMP-induced osteoblast differentiation. In fact, LDN193189 inhibits the induction of alkaline phosphatase activity in C2C12 cells by BMP4 even when administered 12 h after BMP stimulation, indicating sustained BMP signaling activity is needed for osteogenic differentiation.

In the first experiment, LDN193189 (3 mg/kg) is injected intraperitoneally twice a day after tumors became palpable 7 days post-implantation. The growth rates between the control vehicle- and LDN193189-treated mice are not significantly different after the first 5 weeks, but differences in the growth rates are detected after 6 and 7 weeks post-treatment. In the second experiment, cells are isolated from PCa-118b tumors and injected subcutaneously into SCID mice (1×10 ⁶ cells per mouse). LDN193189 or vehicle is applied to mice 5 days post-tumor cell injection before tumors are palpable. The differences in the average growth rates between these two groups, as measured by tumor size, are significant at 6 and 7 weeks post-treatment. The tumor weights also show significant differences at the termination of the study at week 7. The X-ray of the tumors shows that the ectopic bone volume and bone density are reduced in the tumors of LDN193189-treated group compared to that of controls. Co-incubation of pulmonary arterial smooth muscle cells (PASMCs) from the pulmonary arterial hypertension (PAH) rats with UK-92480 and LDN193189 completely inhibited the anti-proliferation and up-regulation of the bone morphogenetic protein (BMPR2) and Cx40 expression by the UK-92480.