Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration

Daisuke Tsugawa, Yuki Oya, Ryota Masuzaki, Kevin Ray, Darren W. Engers, Martin Dib, Nhue Do, Kaori Kuramitsu, Karen Ho, Audrey Frist, Paul B. Yu, Kenneth D. Bloch, Craig W. Lindsley, Corey R. Hopkins, Charles C. Hong, Seth J. Karp

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)549-558
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume351
Issue number3
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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  • Cite this

    Tsugawa, D., Oya, Y., Masuzaki, R., Ray, K., Engers, D. W., Dib, M., Do, N., Kuramitsu, K., Ho, K., Frist, A., Yu, P. B., Bloch, K. D., Lindsley, C. W., Hopkins, C. R., Hong, C. C., & Karp, S. J. (2014). Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration. Journal of Pharmacology and Experimental Therapeutics, 351(3), 549-558. https://doi.org/10.1124/jpet.114.216903