title: 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.
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsugawa
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Oya
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Ryota
authors.initials: R
authors.lastname: Masuzaki
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Ray
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Martin
authors.initials: M
authors.lastname: Dib
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Nhue
authors.initials: N
authors.lastname: Do
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Kaori
authors.initials: K
authors.lastname: Kuramitsu
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Karen
authors.initials: K
authors.lastname: Ho
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Audrey
authors.initials: A
authors.lastname: Frist
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.).
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.affiliation: The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.) seth.karp@vanderbilt.edu.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Karp
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I