Specific Activin Receptor–Like Kinase 3 Inhibitors Enhance Liver Regeneration
| Autor: | Charles C. Hong, Martin J. Dib, Ryota Masuzaki, Audrey Y. Frist, Yuki Oya, Kaori Kuramitsu, Darren W. Engers, Kevin C. Ray, Kenneth D. Bloch, Corey R. Hopkins, Karen J. Ho, Nhue Do, Craig W. Lindsley, Paul B. Yu, Seth J. Karp, Daisuke Tsugawa |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Pharmacology medicine.medical_specialty Kinase Regeneration (biology) SMAD Biology Bone morphogenetic protein Liver regeneration Liver Regeneration Mice Inbred C57BL Mice Endocrinology Internal medicine medicine Animals Humans Molecular Medicine Phosphorylation SOCS3 Receptor Protein Kinase Inhibitors Bone Morphogenetic Protein Receptors Type I Gastrointestinal Hepatic Pulmonary and Renal |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 351:549-558 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.114.216903 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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