Compound C, also known as Dorsomorphin, is a small-molecule inhibitor primarily used in laboratory research to block the activity of AMPK, a key energy-sensing enzyme in cells. It works at very low concentrations, with an IC50 (the amount needed to block half of the enzyme’s activity) of roughly 0.1 to 0.2 µM. Beyond AMPK, Compound C also inhibits bone morphogenetic protein (BMP) signaling and vascular endothelial growth factor (VEGF) receptors, making it a versatile but imprecise research tool with roles in metabolic, cancer, and developmental biology studies.
How Compound C Blocks AMPK
AMPK acts as a cellular fuel gauge. When energy levels drop, AMPK switches on pathways that generate energy (like burning fat and pulling in glucose) and switches off energy-consuming processes (like building new proteins). Compound C directly inhibits AMPK by blocking its ability to become activated through phosphorylation. In cell experiments, treating cells with Compound C at concentrations of 1 to 10 µM for several hours produces a clear reduction in activated AMPK levels.
Researchers use this property to ask a simple question: “What happens when we turn off AMPK?” By comparing cells treated with Compound C to untreated cells, scientists can figure out which biological processes depend on AMPK activity. This approach has been applied across dozens of research areas, from diabetes and obesity to heart disease and cancer.
Inhibition of BMP Signaling
Compound C was originally discovered in a screen for chemicals that disrupt body axis formation in zebrafish embryos, which is how it earned the name “Dorsomorphin” (referring to dorsal, or back-side, development). It selectively blocks a family of BMP type I receptors called ALK2, ALK3, and ALK6. These receptors normally relay BMP signals into the cell by activating a chain of signaling proteins. Compound C prevents this relay, shutting down BMP-driven gene activity and processes like bone cell formation.
One of the most interesting findings involves iron regulation. BMP signaling in the liver controls the production of hepcidin, a hormone that acts as the body’s master switch for iron absorption. In animal studies, Compound C blocked the liver’s ability to ramp up hepcidin production in response to iron, which led to increased iron levels in the blood. This revealed that BMP receptors play an essential role in how the body maintains iron balance, a discovery with implications for understanding iron-overload disorders and anemia.
Effects on Blood Vessel Growth
Compound C also potently inhibits the VEGF type-2 receptor (known as KDR or Flk1), which is a major driver of new blood vessel formation. In lab tests, it suppressed VEGF-triggered receptor activation in a dose-dependent manner, with an IC50 of about 25 nM, making it an even more potent VEGF inhibitor than it is an AMPK inhibitor. In zebrafish, this translated to visible disruption of blood vessel development.
This “off-target” effect is important for two reasons. First, it means that when researchers use Compound C to study AMPK, some of the results they observe may actually be caused by VEGF pathway inhibition rather than AMPK blockade. Second, it opens the door to using Compound C (or refined versions of it) to study how blood vessel growth is regulated, which is relevant to both cancer and cardiovascular research.
Role in Cancer Research
Compound C triggers programmed cell death and autophagy (the process by which cells digest their own components) in cancer cells. In studies on leukemia cells, treatment with Compound C activated a stress-signaling pathway involving reactive oxygen species and p38 MAPK, which in turn suppressed AMPK and downstream proteins involved in cell survival. The result was autophagy-dependent apoptosis, meaning the self-digestion process actively drove the cancer cells toward death.
Notably, when researchers blocked autophagy in these treated cells, the death rate decreased. Conversely, combining Compound C with rapamycin (an mTOR inhibitor) made the leukemia cells more sensitive to killing. Restoring AMPK expression partially rescued cell survival, confirming that AMPK suppression was central to the toxic effect. These findings have pointed researchers toward the AMPK signaling axis as a potential therapeutic target in acute myeloid leukemia.
Compound C has also been used to study how cancer cells adapt their metabolism when they detach from their normal tissue environment, a key step in metastasis. By altering the metabolic fingerprint of detached cancer cells, Compound C helps researchers map the energy pathways that tumors exploit to survive and spread.
Use in Metabolic Studies
Because AMPK is central to glucose and fat metabolism, Compound C is widely used to test whether a given metabolic effect depends on AMPK. In a typical experiment, researchers expose muscle cells to a compound suspected of increasing glucose uptake, then repeat the experiment with Compound C present. If glucose uptake drops in the presence of Compound C, that confirms the effect runs through AMPK. This approach has been used to validate the mechanisms of natural compounds, drug candidates, and exercise-mimicking interventions in cell and tissue models.
Selectivity Limitations
The biggest caveat with Compound C is that it hits many kinases beyond AMPK. In comprehensive kinase-screening assays, it inhibits ALK2 (a BMP receptor), KDR (the VEGF receptor), and AMPK all at concentrations below 250 nM. It also affects additional kinases that have not been as thoroughly cataloged. This means any experiment using Compound C alone cannot definitively attribute a result to AMPK inhibition. Researchers typically need to confirm findings with genetic approaches, such as knocking out the AMPK gene, or with complementary pharmacological tools.
A newer alternative called SBI-0206965 inhibits AMPK with roughly 40-fold greater potency and far less activity against unrelated kinases. Its crystal structure bound to the AMPK kinase domain has been solved, confirming it works through a distinct binding mechanism. For studies where clean AMPK inhibition is critical, SBI-0206965 is increasingly replacing Compound C. Still, Compound C remains the most widely cited AMPK inhibitor in the literature, and much of what we know about AMPK biology was initially mapped using it.