KMN-80

Description

The prostaglandin E receptor 4 (EP₄) is one of four G protein-coupled receptors that mediate the actions of prostaglandin E₂ (PGE₂; ). Binding of PGE₂ to the EP₄ receptor causes an increase in intracellular cyclic AMP, which plays important roles in bone formation and resorption, cancer, and atherosclerosis.^1,2,3,4 KMN-80 is a substituted γ-lactam (pyrrolidinone) derivative of PGE₁ that acts as a selective and potent agonist of EP₄ with an IC₅₀ value of 3 nM (IC₅₀ = 1.4 μM for EP₃ and > 10 μM for all other prostanoid receptors).⁵ In functional assays it has been shown to stimulate secreted alkaline phosphatase gene reporter activity in EP₄-transfected HEK293 cells with an EC₅₀ value of 0.19 nM, demonstrating >5,000 and 50,000-fold selectivity against EP₂ and TP, respectively.⁵ KMN-80 can induce the differentiation of bone marrow stem cells from both young and aged rats into osteoblasts in vitro (EC₅₀s = 20 and 153 nM, respectively) and exhibits favorable tolerability up to at least 10 μM, whereas the EP₄ agonist L-902,688 is highly cytotoxic at similar concentrations in these cells.⁶ KMN-80 has been used to repair calvarial defects in an in vivo rat craniomaxillofacial reconstruction model (rate of reduction in defect size equivalent to BMP-2 treated rats) and to promote bone formation in a rat incisor tooth socket model.⁶

References

1. Li, M., Thompson, D.D., and Paralkar, V.M. Prostaglandin E₂ receptors in bone formation Int. Orthop. 31(6),767-772(2007).
2. Hawcroft, G., Ko, C.W.S., and Hull, M.A. Prostaglandin E₂-EP₄ receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells Oncogene 26(21),3006-3019(2007).
3. Babaev, V.R., Chew, J.D., Ding, L., et al. Macrophage EP₄ deficiency increases apoptosis and suppresses early atherosclerosis Cell Metab. 8(6),492-501(2008).
4. Konya, V., Marsche, G., Schuligoi, R., et al. E-type prostanoid receptor 4 (EP₄) in disease and therapy Pharmacol. Ther. 138(3),485-502(2013).
5. Barrett, S.D., Ciske, F.L., Endres, G.W., et al. Novel Potent Lactam Acetylene EP₄ Agonists Stimulate Alkaline Phosphatase Production and Differentiation in Bone Marrow Cells ,(2014).
6. O'Malley, J., Uzieblo, A., Germain, B.D., et al. Development of a novel prostaglandin EP₄ agonist which stimulates local bone formation in vivo ,(2014).