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Charles C Hong - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective M
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Darren W. Engers, Charles C Hong, Craig W. Lindsley, Audrey Y. Frist, Corey R. HopkinsAbstract:Abstract A structure–activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors Dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.
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DMH1, a Novel BMP Small Molecule Inhibitor, Increases Cardiomyocyte Progenitors and Promotes Cardiac Differentiation in Mouse Embryonic Stem Cells
PloS one, 2012Co-Authors: Jijun Hao, Corey R. Hopkins, Charles C HongAbstract:The possibility of using cell-based therapeutics to treat cardiac failure has generated significant interest since the initial introduction of stem cell-based technologies. However, the methods to quickly and robustly direct stem cell differentiation towards cardiac cell types have been limited by a reliance on recombinant growth factors to provide necessary biological cues. We report here the use of Dorsomorphin homologue 1 (DMH1), a second-generation small molecule BMP inhibitor based on Dorsomorphin, to efficiently induce beating cardiomyocyte formation in mouse embryonic stem cells (ESCs) and to specifically upregulate canonical transcriptional markers associated with cardiac development. DMH1 differs significantly from its predecessor by its ability to enrich for pro-cardiac progenitor cells that respond to late-stage Wnt inhibition using XAV939 and produce secondary beating cardiomyocytes. Our study demonstrates the utility of small molecules to complement existing in vitro cardiac differentiation protocols and highlights the role of transient BMP inhibition in cardiomyogenesis.
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application of small organic molecules reveals cooperative tgfβ and bmp regulation of mesothelial cell behaviors
ACS Chemical Biology, 2011Co-Authors: Emily E Cross, Charles C Hong, Corey R. Hopkins, Rebecca T Thomason, Mitchell Martinez, David M BaderAbstract:Epicardial development is a process during which epithelial sheet movement, single cell migration, and differentiation are coordinated to generate coronary arteries. Signaling cascades regulate the concurrent and complex nature of these three events. Through simple and highly reproducible assays, we identified small organic molecules that impact signaling pathways regulating these epicardial behaviors. Subsequent biochemical analyses confirmed the specificity of these reagents and revealed novel targets for the widely used Dorsomorphin (DM) and LDN-193189 molecules. Using these newly characterized reagents, we show the broad regulation of epicardial cell differentiation, sheet movement, and single cell migration by Transforming Growth Factor β (TGFβ). With the DM analogue DMH1, a highly specific Bone Morphogenetic Protein (BMP) inhibitor, we demonstrate the cooperative yet exclusive role for BMP signaling in regulation of sheet migration. The action of DMH1 reveals that small organic molecules (SOM) can i...
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BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model.
Neurobiology of disease, 2010Co-Authors: Songting Shi, Charles C Hong, Herbert Y Lin, Willem M.h. Hoogaars, David J. J. De Gorter, Sandra H. Van Heiningen, Dwi U. Kemaladewi, Annemieke Aartsma-rus, Peter Ten Dijke, Peter A. C. 't HoenAbstract:Duchenne Muscular Dystrophy (DMD) is an X-linked lethal muscle wasting disease characterized by muscle fiber degeneration and necrosis. The progressive pathology of DMD can be explained by an insufficient regenerative response resulting in fibrosis and adipose tissue formation. BMPs are known to inhibit myogenic differentiation and in a previous study we found an increased expression of a BMP family member BMP4 in DMD myoblasts. The aim of the current study was therefore to investigate whether inhibition of BMP signaling could be beneficial for myoblast differentiation and muscle regeneration processes in a DMD context. All tested BMP inhibitors, Noggin, Dorsomorphin and LDN-193189, were able to accelerate and enhance myogenic differentiation. However, Dorsomorphin repressed both BMP and TGFβ signaling and was found to be toxic to primary myoblast cell cultures. In contrast, Noggin was found to be a potent and selective BMP inhibitor and was therefore tested in vivo in a DMD mouse model. Local adenoviral-mediated overexpression of Noggin in muscle resulted in an increased expression of the myogenic regulatory genes Myog and Myod1 and improved muscle histology. In conclusion, our results suggest that repression of BMP signaling may constitute an attractive adjunctive therapy for DMD patients.
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In vivo structure-activity relationship study of Dorsomorphin analogues identifies selective VEGF and BMP inhibitors.
ACS chemical biology, 2010Co-Authors: Jijun Hao, Jana A. Lewis, Kaleh A. Karim, R. Nathan Daniels, Patrick R. Gentry, Corey R. Hopkins, Craig W. Lindsley, Charles C HongAbstract:The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we identified Dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that Dorsomorphin has significant “off-target” effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether Dorsomorphin’s antiangiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogues that target BMP but not VEGF signaling and vice versa. In a structure−activity relationship (SAR) study of Dorsomorphin analogues based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the...
Corey R. Hopkins - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective M
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Darren W. Engers, Charles C Hong, Craig W. Lindsley, Audrey Y. Frist, Corey R. HopkinsAbstract:Abstract A structure–activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors Dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.
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DMH1, a Novel BMP Small Molecule Inhibitor, Increases Cardiomyocyte Progenitors and Promotes Cardiac Differentiation in Mouse Embryonic Stem Cells
PloS one, 2012Co-Authors: Jijun Hao, Corey R. Hopkins, Charles C HongAbstract:The possibility of using cell-based therapeutics to treat cardiac failure has generated significant interest since the initial introduction of stem cell-based technologies. However, the methods to quickly and robustly direct stem cell differentiation towards cardiac cell types have been limited by a reliance on recombinant growth factors to provide necessary biological cues. We report here the use of Dorsomorphin homologue 1 (DMH1), a second-generation small molecule BMP inhibitor based on Dorsomorphin, to efficiently induce beating cardiomyocyte formation in mouse embryonic stem cells (ESCs) and to specifically upregulate canonical transcriptional markers associated with cardiac development. DMH1 differs significantly from its predecessor by its ability to enrich for pro-cardiac progenitor cells that respond to late-stage Wnt inhibition using XAV939 and produce secondary beating cardiomyocytes. Our study demonstrates the utility of small molecules to complement existing in vitro cardiac differentiation protocols and highlights the role of transient BMP inhibition in cardiomyogenesis.
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application of small organic molecules reveals cooperative tgfβ and bmp regulation of mesothelial cell behaviors
ACS Chemical Biology, 2011Co-Authors: Emily E Cross, Charles C Hong, Corey R. Hopkins, Rebecca T Thomason, Mitchell Martinez, David M BaderAbstract:Epicardial development is a process during which epithelial sheet movement, single cell migration, and differentiation are coordinated to generate coronary arteries. Signaling cascades regulate the concurrent and complex nature of these three events. Through simple and highly reproducible assays, we identified small organic molecules that impact signaling pathways regulating these epicardial behaviors. Subsequent biochemical analyses confirmed the specificity of these reagents and revealed novel targets for the widely used Dorsomorphin (DM) and LDN-193189 molecules. Using these newly characterized reagents, we show the broad regulation of epicardial cell differentiation, sheet movement, and single cell migration by Transforming Growth Factor β (TGFβ). With the DM analogue DMH1, a highly specific Bone Morphogenetic Protein (BMP) inhibitor, we demonstrate the cooperative yet exclusive role for BMP signaling in regulation of sheet migration. The action of DMH1 reveals that small organic molecules (SOM) can i...
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In vivo structure-activity relationship study of Dorsomorphin analogues identifies selective VEGF and BMP inhibitors.
ACS chemical biology, 2010Co-Authors: Jijun Hao, Jana A. Lewis, Kaleh A. Karim, R. Nathan Daniels, Patrick R. Gentry, Corey R. Hopkins, Craig W. Lindsley, Charles C HongAbstract:The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we identified Dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that Dorsomorphin has significant “off-target” effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether Dorsomorphin’s antiangiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogues that target BMP but not VEGF signaling and vice versa. In a structure−activity relationship (SAR) study of Dorsomorphin analogues based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the...
Michael Forgac - One of the best experts on this subject based on the ideXlab platform.
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akt ser thr kinase increases v atpase dependent lysosomal acidification in response to amino acid starvation in mammalian cells
Journal of Biological Chemistry, 2020Co-Authors: Michael Collins, Laura A Stransky, Michael ForgacAbstract:The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that is essential for cellular homeostasis. V-ATPase activity is controlled by the regulated assembly of the enzyme from its component V1 and V0 domains. We previously reported that amino acid starvation rapidly increases V-ATPase assembly and activity in mammalian lysosomes, but the signaling pathways controlling this effect are unknown. In testing inhibitors of pathways important for controlling cellular metabolism, we found here that the cAMP-dependent protein kinase (PKA) inhibitor H89 increases lysosomal V-ATPase activity and blocks any further change upon starvation. The AMP-activated protein kinase (AMPK) inhibitor Dorsomorphin decreased lysosomal V-ATPase activity and also blocked any increase upon starvation. However, CRISPR-mediated gene editing revealed that PKA and AMPK are not required for the starvation-dependent increase in lysosomal V-ATPase activity, indicating that H89 and Dorsomorphin modify V-ATPase activity through other cellular targets. We next found that the AKT Ser/Thr kinase (AKT) inhibitor MK2206 blocks the starvation-dependent increase in lysosomal V-ATPase activity without altering basal activity. Expression of AKT1 or AKT3, but not AKT2, was required for increased lysosomal V-ATPase activity in response to amino acid starvation in mouse fibroblasts. Finally, HEK293T cells expressing only AKT1 responded normally to starvation, whereas cells expressing only AKT2 displayed a significantly reduced increase in V-ATPase activity and assembly upon starvation. These results show that AKT is required for controlling the rapid response of lysosomal V-ATPase activity to changes in amino acid availability and that this response depends on specific AKT isoforms.
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AKT Ser/Thr kinase increases V-ATPase–dependent lysosomal acidification in response to amino acid starvation in mammalian cells
The Journal of biological chemistry, 2020Co-Authors: Michael Collins, Laura A Stransky, Michael ForgacAbstract:The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that is essential for cellular homeostasis. V-ATPase activity is controlled by the regulated assembly of the enzyme from its component V1 and V0 domains. We previously reported that amino acid starvation rapidly increases V-ATPase assembly and activity in mammalian lysosomes, but the signaling pathways controlling this effect are unknown. In testing inhibitors of pathways important for controlling cellular metabolism, we found here that the cAMP-dependent protein kinase (PKA) inhibitor H89 increases lysosomal V-ATPase activity and blocks any further change upon starvation. The AMP-activated protein kinase (AMPK) inhibitor Dorsomorphin decreased lysosomal V-ATPase activity and also blocked any increase upon starvation. However, CRISPR-mediated gene editing revealed that PKA and AMPK are not required for the starvation-dependent increase in lysosomal V-ATPase activity, indicating that H89 and Dorsomorphin modify V-ATPase activity through other cellular targets. We next found that the AKT Ser/Thr kinase (AKT) inhibitor MK2206 blocks the starvation-dependent increase in lysosomal V-ATPase activity without altering basal activity. Expression of AKT1 or AKT3, but not AKT2, was required for increased lysosomal V-ATPase activity in response to amino acid starvation in mouse fibroblasts. Finally, HEK293T cells expressing only AKT1 responded normally to starvation, whereas cells expressing only AKT2 displayed a significantly reduced increase in V-ATPase activity and assembly upon starvation. These results show that AKT is required for controlling the rapid response of lysosomal V-ATPase activity to changes in amino acid availability and that this response depends on specific AKT isoforms.
Randall T Peterson - One of the best experts on this subject based on the ideXlab platform.
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Dorsomorphin a selective small molecule inhibitor of bmp signaling promotes cardiomyogenesis in embryonic stem cells
PLOS ONE, 2008Co-Authors: Marie A Daleo, Randall T Peterson, Clare K Murphy, Paul B Yu, Joshua N Ho, Jianyong Hu, Antonis K Hatzopoulos, Charles C HongAbstract:Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/ Principal Findings: We describe the use of Dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. QuantitativePCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/ Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like Dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine.
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structure activity relationship study of bone morphogenetic protein bmp signaling inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Gregory D Cuny, Chetana Sachidanandan, Donna Y Deng, Kenneth D Bloch, Joydev K Laha, Xuechao Xing, Jifeng Liu, Carol S Lai, Randall T PetersonAbstract:A structure-activity relationship study of Dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t(1/2)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.
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Dorsomorphin inhibits bmp signals required for embryogenesis and iron metabolism
Nature Chemical Biology, 2008Co-Authors: Charles C Hong, Chetana Sachidanandan, Jodie L Babitt, Donna Y Deng, Stefan A Hoyng, Herbert Y Lin, Kenneth D Bloch, Randall T PetersonAbstract:Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling—Dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that Dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using Dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, Dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6–stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with Dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.
Haruhide Hayashi - One of the best experts on this subject based on the ideXlab platform.
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Effects of the Small Molecule Dorsomorphin on Intracellular Signaling
Interface Oral Health Science 2011, 2012Co-Authors: Tada-aki Kudo, Hiroyasu Kanetaka, Kazutoshi Mizuno, Yasuhiro Ryu, Ye Zhang, Mitsuhiro Kano, Yoshinaka Shimizu, Haruhide HayashiAbstract:The small molecule Dorsomorphin, also known as compound C, is a cell-permeable pyrazolopyrimidine derivative, which acts as a potent and reversible ATP-competitive inhibitor of AMP-activated protein kinase (AMPK). Recent studies indicated that several molecules with functions in other signaling pathways, including bone morphogenetic protein (BMP) signaling, are novel targets of Dorsomorphin. This report focuses on two major targets of Dorsomorphin and provides insight into the use of Dorsomorphin in the analysis of intracellular signaling.
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Dorsomorphin stimulates neurite outgrowth in pc12 cells via activation of a protein kinase a dependent mek erk1 2 signaling pathway
Genes to Cells, 2011Co-Authors: Tada-aki Kudo, Hiroyasu Kanetaka, Kazutoshi Mizuno, Yasuhiro Ryu, Yoshiyuki Miyamoto, Shoko Nunome, Ye Zhang, Mitsuhiro Kano, Yoshinaka Shimizu, Haruhide HayashiAbstract:In this study, we investigated the effect of Dorsomorphin, a selective inhibitor of bone morphogenetic protein (BMP) signaling, on rat PC12 pheochromocytoma cell differentiation. PC12 cells can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor, BMP2, and other inducers. Cells were incubated with BMP2 and/or Dorsomorphin, and the extent of neurite outgrowth was evaluated. Unexpectedly, BMP2-mediated neuritogenesis was not inhibited by co-treatment with Dorsomorphin. We also found that treatment with Dorsomorphin alone, but not another BMP signaling inhibitor, LDN-193189, induced neurite outgrowth in PC12 cells. To further understand the mechanism of action of Dorsomorphin, the effects of this drug on intracellular signaling were investigated using the following signaling inhibitors: the ERK kinase (MEK) inhibitor U0126; the tropomyosin-related kinase A inhibitor GW441756; and the protein kinase A (PKA) inhibitor H89. Dorsomorphin induced rapid and sustained ERK1/2 activation; however, Dorsomorphin-mediated ERK1/2 activation and neuritogenesis were robustly inhibited in the presence of U0126 or H89, but not GW441756. These findings suggest that Dorsomorphin has the potential to induce neuritogenesis in PC12 cells, a response that requires the activation of PKA-dependent MEK-ERK1/2 signaling.
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Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A‐dependent MEK‐ERK1/2 signaling pathway
Genes to cells : devoted to molecular & cellular mechanisms, 2011Co-Authors: Tada-aki Kudo, Hiroyasu Kanetaka, Kazutoshi Mizuno, Yasuhiro Ryu, Yoshiyuki Miyamoto, Shoko Nunome, Ye Zhang, Mitsuhiro Kano, Yoshinaka Shimizu, Haruhide HayashiAbstract:In this study, we investigated the effect of Dorsomorphin, a selective inhibitor of bone morphogenetic protein (BMP) signaling, on rat PC12 pheochromocytoma cell differentiation. PC12 cells can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor, BMP2, and other inducers. Cells were incubated with BMP2 and/or Dorsomorphin, and the extent of neurite outgrowth was evaluated. Unexpectedly, BMP2-mediated neuritogenesis was not inhibited by co-treatment with Dorsomorphin. We also found that treatment with Dorsomorphin alone, but not another BMP signaling inhibitor, LDN-193189, induced neurite outgrowth in PC12 cells. To further understand the mechanism of action of Dorsomorphin, the effects of this drug on intracellular signaling were investigated using the following signaling inhibitors: the ERK kinase (MEK) inhibitor U0126; the tropomyosin-related kinase A inhibitor GW441756; and the protein kinase A (PKA) inhibitor H89. Dorsomorphin induced rapid and sustained ERK1/2 activation; however, Dorsomorphin-mediated ERK1/2 activation and neuritogenesis were robustly inhibited in the presence of U0126 or H89, but not GW441756. These findings suggest that Dorsomorphin has the potential to induce neuritogenesis in PC12 cells, a response that requires the activation of PKA-dependent MEK-ERK1/2 signaling.