Last update 01 Nov 2024

BMPR1A x ALK2

Last update 01 Nov 2024

Basic Info

Related Targets

BMPR1AALK2

Drugs associated with BMPR1A x ALK2

LJ000328

Target

ALK2 x BMPR1A

Mechanism

ALK2 inhibitors [+1]

Active Org.

La Jolla Pharmaceutical Co.

Originator Org.

La Jolla Pharmaceutical Co.

Active Indication

Iron-Refractory Iron Deficiency Anemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ML-347

Target

ALK2 x BMPR1A

Mechanism

ALK2 inhibitors [+1]

Active Org.-

Originator Org.

Vanderbilt University

Active Indication-

Inactive Indication

Myositis Ossificans

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BMPR1A x ALK2

100 Translational Medicine associated with BMPR1A x ALK2

0 Patents (Medical) associated with BMPR1A x ALK2

170

Literatures (Medical) associated with BMPR1A x ALK2

11 Jun 2024·Blood Advances

Hemojuvelin-mediated hepcidin induction requires both bone morphogenetic protein type I receptors ALK2 and ALK3

Article

Author: Gradhand, Elise ; Zacharowski, Kai ; Oguama, David ; Klingmüller, Ursula ; Urzica, Eugen I ; von Knethen, Andreas ; Dogan, Deniz Y ; Popp, Rüdiger ; Nguyen, Lien H ; Schrader, Lisa ; Steinbicker, Andrea U ; Fette, Franca M ; Hornung, Isabelle ; Fleming, Ingrid ; Kastl, Philipp ; Rosenbauer, Frank

AbstractHemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) levels, soluble HJV (sHJV), splenic iron content (SIC), as well as phosphorylated small mothers against decapentaplegic protein (pSMAD1/5/8) levels. In contrast, in Alk2fl/fl;Alb-Cre and Alk3fl/fl;Alb-Cre mice, which present with moderate and severe iron overload, respectively, the administration of AAV-HJV induced HJV and sHJV. However, it did not rescue the iron overload phenotypes of those mice. Serum iron levels were induced in Alk2fl/fl;Alb-Cre mice after HJV overexpression. In phosphate-buffered saline–injected Alk3fl/fl;Alb-Cre mice, serum iron levels and the expression of duodenal ferroportin remained high, whereas Hamp mRNA levels were decreased to 1% to 5% of the levels detected in controls. This was reduced even further by AAV-HJV overexpression. SIC remained low in mice with hepatocyte-specific Alk2 or Alk3 deficiency, reflecting disturbed iron homeostasis with high serum iron levels and transferrin saturation and an inability to induce hepcidin by HJV overexpression. The data indicate that ALK2 and ALK3 are both required in vivo for the HJV-mediated induction of hepcidin.

29 May 2024·Science Translational Medicine

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva

Article

Author: LaBranche, Timothy P ; Zhu, Xing Julia ; Dorsch, Marion ; Lengauer, Christoph ; Davis, Alison J ; Palmer, Michael ; Stevison, Faith ; Garner, Andrew P ; Stewart, Rachel ; Albayya, Faris ; Vassiliadis, John ; Hodous, Brian L ; Xu, Lan ; Brubaker, Jason D ; Fleming, Paul ; Wang, Ruduan ; Guzi, Timothy J ; Lobbardi, Riadh ; Sheets, Michael P ; Wilson, Douglas ; Hunter, Jeffrey W ; Brooijmans, Natasja ; Williams, Brett D ; Kim, Joseph L ; Kim, Sean ; Bouchard, Keith ; Kadambi, Vivek ; Russo, Joelle ; Graul, Chris ; Hussein, Amira ; Greenblatt, Elliot ; Lyon, Morgan

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor–like kinase 2 (ALK2), the most common variant being ALK2 R206H . In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2 R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2 R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2 R206H with high affinity, inhibiting signaling from ALK2 R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2 R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2 R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2 R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

01 May 2024·Redox Biology

Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury

Article

Author: Cubero, Francisco Javier ; Rey, Esther ; Valverde, Ángela M ; Ramos, Sonia ; Martín, María Ángeles ; González-Rodríguez, Águeda ; Rada, Patricia ; Choya-Foces, Carmen ; Wu, Hanghang ; Martínez-Ruiz, Antonio ; García-Monzón, Carmelo ; Marañón, Patricia ; Isaza, Stephania C

Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF.

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