AMPK (AMP-activated protein kinase) is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins (subunits) that together make a functional enzyme. Importantly, AMPK plays a role in the phosphorylation and inactivation of key enzymes such as acetyl-coenzyme A carboxylase (ACC), and is a major regulator of lipid biosynthesis pathways. AMPK acts as a metabolic master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids and the biogenesis of glucose transporter 4 (GLUT4) and mitochondria.
Dorsomorphin (also known as Compound C or BML-275) is a selective, reversible and ATP-competitive AMPK inhibitor. However, Dorsomorphin shows no significant inhibitory effect on several structurally related kinases, including ZAPK, SYK, PKCθ, PKA and JAK3). In addition, Dorsomorphin selectively inhibits BMP type I receptors ALK2, ALK3, and ALK6. And this compound also induces autophagy. Incubation of cultured hepatocytes with Dorsomorphin inhibits acetyl-CoA carboxylase inactivation by either AICAR or metformin. Importantly, coincubation of hepatocytes with Dorsomorphin is able to attenuate the effects of metformin to decrease glucose production in these cells. Moreover, Dorsomorphin inhibits the expression of ICAM-1 and VCAM-1 at the transcription and translation level by inhibiting the activities of PI3K, p38MAPK and NF-κB in human umbilical vein endothelial cells (HUVEC) in response to TNF-α in vitro.
All in all, Dorsomorphin is a selective, reversible and ATP-competitive AMPK inhibitor, and selectively inhibits BMP type I receptors ALK2, ALK3, and ALK6.
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