Specific Activin Receptor–Like Kinase 3 Inhibitors Enhance Liver Regeneration

Abstract

Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl) phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a] pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.

Bone Morphogenetic Proteins

“…Through a highthroughput screening, a stimulator of BMP signaling has been discovered, while its mode of action has not been elucidated (Balaramnavar et al 2012). Like BMP agonists, small molecule inhibitors specific for BMP signaling have been developed (Yu et al 2008a;Hong and Yu 2009;Boergermann et al 2010;Mohedas et al 2013;Sanvitale et al 2013;Tsugawa et al 2014). These inhibitors appear to be useful for the treatment of various diseases that are caused by activation of BMP signals, such as FOP (Yu et al 2008b), DIPG (Pacifici and Shore 2016), and metastasis in certain types of cancer.…”

Effect of Secreted Molecules of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells on Acute Hepatic Failure Model

“…More importantly, BMP4 and VEGF molecules were associated with biological processes such as regulation of epithelial cell proliferation and the immune system process, as well as negative regulation of the apoptotic process. Recent studies showed that BMP4 was a paracrine inhibitor of liver regeneration [26][27][28]. VEGF, a trophic factor, has emerged as an important mediator of immune tolerance in the tumor microenvironment [29].…”

Bone morphogenetic protein type I receptor inhibition induces cleft palate associated with micrognathia and cleft lower lip in mice

“…As a complementary strategy to genetic approaches, LDN-193189 used to modulate BMP signaling in vivo may have greater flexibility and lower cost (Hong and Yu, 2009). Because the optimal teratogenic concentration of LDN-193189 in mice remained unknown, we tested the dosages of 3 mg/kg, 6 mg/kg, and 9 mg/kg by in vivo injection twice per day, as was reported previously Peterson et al, 2014;Tsugawa et al, 2014). Considering the fact that embryos exposed to the dose of 6 mg/ kg had the highest rate of visible facial defects, tolerable rate of early embryonic lethality with no obvious embryo toxicity, we chose this dose for our studies.…”