LDN-193189 is a highly potent small molecule inhibitor of bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 with IC50 values of 5 nM and 30 nM, respectively. BMPs induce Smad1/5/8 plus non-Smad pathways, such as MAPK and Akt. BMP signaling pathway is the key regulators of cell fate decisions during embryogenesis and tissue homeostasis. LDN-193189 inhibits ectopic ossification and a potential agent in the treatment of NSCLC lung tumors, showing significant in vivo clinical utility. In addition, it inhibits the activation of p38, ERK1/2 and Akt in C2C12 cells. LDN-193189 only weakly inhibits ALK4, ALK5, and ALK7. LDN-193189 affects not only the Smad but also the non-Smad signalling pathways induced by either BMP2, BMP6 or GDF5.
|Cell lines||C2C12 cells|
|Preparation method||Alkaline phosphatase activity We seeded C2C12 cells into 96-well plates at 2,000 cells per well in DMEM supplemented with 2% FBS. We treated the wells in quadruplicate with BMP ligands and LDN-193189 or vehicle. We collected the cells after 6 d in culture in 50 μl Tris-buffered saline and 1% Triton X-100. We added the lysates to p-nitro-phenylphosphate reagent in 96-well plates (Sigma) for 1 h and then evaluated alkaline phosphatase activity (absorbance at 405 nm). We measured cell viability and quantity by Cell Titer Aqueous One (absorbance at 490 nm, Promega), using replicate wells treated identically to those used for alkaline phosphatase measurements.|
|Incubation time||6 days|
|Animal models||C57BL/6 mouse FOP model|
|Dosages||3 mg /kg every 12 h|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||Water ≥30 mg/mL|
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