6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE

Description

Dorsomorphin (866405-64-3) is a potent, selective and ATP-competitive inhibitor of AMP-activated protein kinase (AMPK) (Ki = 109 nM).1 It displays no significant inhibition of ZAPK, SYK, PKCT, PKA and JAK3. It inhibits bone morphogenetic protein (BMP) type I receptors (ALK2, ALK3 and ALK6).2 Dorsomorphin has been shown to promote cardiomyogenesis in mouse embryonic stem cells (ESCs) in vitro.3 Dorsomorphin also induces autophagy in cancer cell lines via a mechanism independent of AMPK inhibition.4

Uses

Dorsomorphin has been used:

• as an inhibitor of adenosine monophosphate-activated protein kinase (AMPK) to find the effects of trans-resveratrol on lipid mobilization in 3T3-L1 (a murine cell line of adipocytes) cells
• as an AMPK inhibitor, to indicate the involvement of AMPK/mTOR (mammalian target of rapamycin) pathway in LRG (liraglutide) -induced autophagy
• in the induction step, employed in in vitro differentiation of Friedreich′s ataxia (FRDA) and induced pluripotent stem cells (iPSCs) to neurospheres and neurons using ES (embryonic stem cell) media

Uses

A potent inhibitor of AMPK and fatty acid biosynthesis.

Definition

ChEBI: A pyrazolopyrimidine that is pyrazolo[1,5-a]pyrimidine which is substituted at positions 3 and 6 by pyridin-4-yl and p-[2-(piperidin-1-yl)ethoxy]phenyl groups, respectively. It is a potent, selective, reversible, and ATP-competiti e inhibitor of AMPK (AMP-activated protein kinase, EC 2.7.11.31) and a selective inhibitor of bone morphogenetic protein (BMP) signaling.

General Description

A cell-permeable pyrrazolopyrimidine compound that inhibits against KDR/VEGFR2, ALK2/BMPR-I, AMPK kinase activity (IC₅₀ = 25.1, 148, and 234.6 nM, respectively), while exhibiting much reduced or little effect toward ALK5/TGFβR-I, ZAPK, Syk, PKCθ, PKA, or JAK3. Shown to block both BMP pathway-dependent dorsoventral development (EC₁₀₀ = 2.5 μM) and VEGF signaling-dependent intersomitic vessel formation (EC₅₀ = 5 μM) in zebrafish embryo in vivo. Commonly used in combination with AMPK activators AICAR (Cat. No. 123040) and/or Metformin (Cat. No. 317240) for studying AMPK-dependent cellular events in vitro and physiological responses in animals in vivo.

Biological Activity

Potent and selective inhibitor of AMP-activated protein kinase (AMPK) (K i = 109 nM). Displays no significant activity on several structurally related kinases including ZAPK, SYK, PKC θ , PKA and JAK3. Inhibits AMPK activation induced by AICAR and metformin. Also inhibits bone morphogenic protein (BMP) type I receptors (ALK2, ALK3 and ALK6). Promotes cardiomyogenesis in mouse embryonic stem cells (ESCs) in vitro .

Biochem/physiol Actions

Target IC50: 25.1, 148, and 234.6 nM, against KDR/VEGFR2, ALK2/BMPR-I, AMPK kinase activity, respectively

References

[1] ZHOU G, MYERS R W, LI Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action.[J]. The Journal of clinical investigation, 2001, 1 1: 0. DOI:10.1172/jci13505
[2] PAUL B YU. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism[J]. Nature chemical biology, 2007, 4 1: 33-41. DOI:10.1038/nchembio.2007.54
[3] JIJUN HAO. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells.[J]. PLoS ONE, 2008, 3 8: e2904. DOI:10.1371/journal.pone.0002904
[4] LJUBICA VUCICEVIC. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway.[J]. Autophagy, 2011, 7 1: 40-50. DOI:10.4161/auto.7.1.13883