Dorsomorphin (Compound C) (Synonyms: Compound C)

Dorsomorphin (Compound C) is a potent, cell-permeable dual inhibitor of AMPK and BMP pathways (K_i value of 109nM for AMPK).Dorsomorphin competitively binds to the ATP site of AMPK to inhibit AMPK activity and block cellular energy sensing. At the same time, Dorsomorphin inhibits BMP type I receptors ALK2/ALK3/ALK6 to block SMAD1/5/8 phosphorylation. Dorsomorphin can be used in stem cell differentiation, tumor and metabolism research^[1-4].

In vitro, Dorsomorphin (5μM) treated Jurkat, U937, Molt4 and other acute lymphoblastic leukemia and acute myeloid leukemia cell lines for 24h. Dorsomorphin inhibited AMPKα autophosphorylation and phosphorylation of downstream AMPK substrates including Beclin 1, Raptor, ULK1, ACC in cells. Dorsomorphin enhanced mitochondrial pathway cell death^[5]. Dorsomorphin (5μM) combined with differentiation inducers (3-isobutyl-1-methylxanthine 0.5mM, dexamethasone 0.25μM, insulin 10μg/ml) treated 3T3-L1 preadipocytes for 8 days. Dorsomorphin significantly reduced lipid accumulation in 3T3-L1 preadipocytes^[6].

In vivo, Dorsomorphin (10mg/kg; single tail vein injection) combined with recombinant human GPNMB (rGPNMB; single intracerebroventricular injection) was given to CD-1 male mice with subarachnoid hemorrhage (SAH) model at 1h after SAH modeling. Dorsomorphin reduced the p-AMPK/AMPK ratio in mice. Dorsomorphin reversed the downregulation of p-NFκB, IL-1β, IL-6 and TNF-α caused by rGPNMB. Dorsomorphin counteracted the alleviation of brain edema, blood-brain barrier disruption and neurological deficits mediated by rGPNMB^[7]. Dorsomorphin (10mg/kg) was intraperitoneally injected into APP/PS1 mice 1h before each aerobic exercise session for 8 weeks. Dorsomorphin eliminated the promotion of p300 nuclear translocation, upregulation of hippocampal H4K5ac and H4K12ac, and enrichment of histone acetylation at GluN1 promoter region induced by aerobic exercise. Dorsomorphin counteracted the improvements in CA1 dendritic spine density, LTP and contextual fear memory enhanced by aerobic exercise^[8].

References:

[1] Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001 Oct;108(8):1167-74.

[2] Kim YM, Kim MY, Kim HJ, et al. Compound C independent of AMPK inhibits ICAM-1 and VCAM-1 expression in inflammatory stimulants-activated endothelial cells in vitro and in vivo. Atherosclerosis. 2011 Nov;219(1):57-64.

[3] Saito S, Furuno A, Sakurai J, et al. Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling. PLoS One. 2012;7(9):e45845.

[4] Guo Y, Zhang Y, Hong K, et al. AMPK inhibition blocks ROS-NFκB signaling and attenuates endotoxemia-induced liver injury. PLoS One. 2014 Jan 24;9(1):e86881.

[5] Jia J, Ji W, Saliba AN, et al. AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. Cell Death Differ. 2024;31(3):405-416.

[6] Suenaga M, Matsui T, Funaba M. BMP Inhibition with Dorsomorphin Limits Adipogenic Potential of Preadipocytes. J Vet Med Sci. 2010;72(3):373-377.

[7] Li T, Zhang Y, Lu Q, et al. GPNMB Ameliorates Neuroinflammation Via the Modulation of AMPK/NFkB Signaling Pathway After SAH in Mice. J Neuroimmune Pharmacol. 2023;18(6):628-639.

[8] Chai G, Gao T, Bi S, et al. Aerobic exercise facilitates p300 nuclear translocation via ADRB2-AMPKα signaling, leading to enhanced histone acetylation and mitigation of cognitive decline in APP/PS1 mice. Alzheimer's Res Ther. 2026;18:62.