A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

Gómez-Galeno, Jorge; Dang, Qun; Nguyen, Thanh H.; Boyer, Serge H.; Grote, Matthew P.; Sun, Zhili; Chen, Mingwei; Craigo, William A.; Poelje, Paul D. van; MacKenna, Deidre A.; Cable, Edward Earl; Rolzin, Paul; Finn, Patricia D.; Chi, Bert; Linemeyer, David L.; Hecker, Scott J.; Erion, Mark D.

doi:10.1021/ml100143q

Cited by 82 publications

(81 citation statements)

References 35 publications

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“…However, AICAR may be useful in treating humans with acute lymphoblastic leukemia59,60 and cardiac ischemic injury 61,62. Interestingly, another recently described AMPK activator, compound 13, is taken up into the cells and converted to the AMP analog, compound 2, which is a much more potent and specific activator of AMPK when compared to ZMP 63. Compounds of this series are being optimized for oral bioavailability and pharmacokinetics; however, their clinical utility remains to be seen 63…”

Section: Ampk Activatorsmentioning

confidence: 99%

AMPK activation: a therapeutic target for type 2 diabetes?

Coughlan¹,

Valentine²,

Ruderman³

et al. 2014

DMSO

219

169

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Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance, β-cell dysfunction, and elevated hepatic glucose output. Over 350 million people worldwide have T2D, and the International Diabetes Federation projects that this number will increase to nearly 600 million by 2035. There is a great need for more effective treatments for maintaining glucose homeostasis and improving insulin sensitivity. AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase whose activation elicits insulin-sensitizing effects, making it an ideal therapeutic target for T2D. AMPK is an energy-sensing enzyme that is activated when cellular energy levels are low, and it signals to stimulate glucose uptake in skeletal muscles, fatty acid oxidation in adipose (and other) tissues, and reduces hepatic glucose production. There is substantial evidence suggesting that AMPK is dysregulated in animals and humans with metabolic syndrome or T2D, and that AMPK activation (physiological or pharmacological) can improve insulin sensitivity and metabolic health. Numerous pharmacological agents, natural compounds, and hormones are known to activate AMPK, either directly or indirectly – some of which (for example, metformin and thiazolidinediones) are currently used to treat T2D. This paper will review the regulation of the AMPK pathway and its role in T2D, some of the known AMPK activators and their mechanisms of action, and the potential for future improvements in targeting AMPK for the treatment of T2D.

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Section: Ampk Activatorsmentioning

confidence: 99%

AMPK activation: a therapeutic target for type 2 diabetes?

Coughlan¹,

Valentine²,

Ruderman³

et al. 2014

DMSO

219

169

View full text Add to dashboard Cite

show abstract

“…As many pharmacological activators of AMPK, including the biguanides metformin [13] and phenformin [38], the thiazolidinedione peroxisome proliferator-activated receptor (PPAR)γ agonist troglitazone and ciglitazone [122], AICAR [123], the natural products berberine [124], resveratrol [125], and curcumin [126], and the direct activators A-769662 [127] and PT-1 [128] (structures, Fig. 2), have been discussed in details in several recent reviews [10, 129–131], we focus here on two of the most recently reported activators, OSU-53 [132] and compound 2 [5-(5-hydroxy-isoxazol-3-yl)-furan-2-phosphnic acid] [133] (structures, Fig. 2).…”

Section: Ampk Modulators As Cancer Therapeutic Agentsmentioning

confidence: 99%

AMPK as a Potential Anticancer Target - Friend or Foe?

Chuang¹,

Chou²,

Kulp³

et al. 2014

CPD

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Adenosine monophosphate-activated protein kinase (AMPK) is a key player in maintaining energy homeostasis in response to metabolic stress. Beyond diabetes and metabolic syndrome, there is a growing interest in the therapeutic exploitation of the AMPK pathway in cancer treatment in light of its unique ability to regulate cancer cell proliferation through the reprogramming of cell metabolism. Although many studies support the tumor-suppressive role of AMPK, emerging evidence suggests that the metabolic checkpoint function of AMPK might be overridden by stress or oncogenic signals so that tumor cells use AMPK activation as a survival strategy to gain growth advantage. These findings underscore the complexity in the cellular function of AMPK in maintaining energy homeostasis under physiological versus pathological conditions. Thus, this review aims to provide an overview of recent findings on the functional interplay of AMPK with different cell metabolic and signaling effectors, particularly histone deacetylases, in mediating downstream tumor suppressive or promoting mechanisms in different cell systems. Although AMPK activation inhibits tumor growth by targeting multiple signaling pathways relevant to tumorigenesis, under certain cellular contexts or certain stages of tumor development, AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation, low oxygen, and low pH, or as a downstream effectors of oncogenic proteins, including androgen receptor, hypoxia-inducible factor-1α, c-Src, and MYC. Thus, investigations to define at which stage(s) of tumorigenesis and cancer progression or for which genetic aberrations AMPK inhibition might represent a more relevant strategy than AMPK activation for cancer treatment are clearly warranted.

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“…One except is A769662, which stimulates b1-containing complexes [29]. Recent research efforts have identified a nucleotide mimetic compound 2 (C2) [30], and its cellpermeable pro-drug C13 [18], as novel and highly potent AMPK activators. C13 is characterized as an a1-selective small molecule activator of AMPK [18].…”

Section: Discussionmentioning

confidence: 99%