Promise and challenges for direct small molecule AMPK activators

Abstract

AMP-activated protein kinase (AMPK) is an evolutionary conserved and ubiquitously expressed serine/threonine kinase playing a central role in the coordination of energy homeostasis. Based on the beneficial outcomes of its activation on metabolism, AMPK has emerged as an attractive target for the treatment of metabolic diseases. Identification of novel downstream targets of AMPK beyond the regulation of energy metabolism has renewed considerable attention in exploiting AMPK signaling for novel therapeutic targeting strategies including treatment of cancer and inflammatory diseases. The complexity of AMPK system with tissue- and species-specific expression of multiple isoform combination regulated by various inputs, post-traductional modifications and subcellular locations presents unique challenges for drug discovery. Here, we review the most recent advances in the understanding of the mechanism(s) of action of direct small molecule AMPK activators and the potential therapeutic opportunities.

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

“…Small molecule AMPmimetics, for example by 5-aminoimidazole-4-carboxamide riboside (AICAR), can activate AMPK allosterically [73]. AMPK can furthermore be activated by a range of specific synthetic AMPK activators [74]. Lastly, the ATP to AMP ratio can be decreased by exercise [75] and caloric restriction [76], indicating an energy-deficient state which activates AMPK.…”

“…However, compound A-769662 has poor bioavailability and thus may not be useful in clinical settings, requiring long-term daily administration. Further β1-selective, γ-selective or pan-AMPK activators have been developed and tested in cancer models and the kidney but not the heart [74] or are in development and have not yet been tested in vivo [165]. It would be interesting to test some of these specific AMPK activators in models of DOX cardiotoxicity to more directly establish the role of AMPK activation in cardioprotection without any offtarget effects.…”

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

“…In view of the essential role of AMPK in different cellular processes, it is not surprising that several pathologies including cancer, metabolic dysfunction, in ammatory disorders and neurodegeneration have been associated with this kinase [3,[9][10][11]. Concerning cancer, pro-tumorigenic and tumor suppressor functions have been reported for AMPK, depending on parameters such as subcellular location, complex members and upstream modulators [12].…”

“…However, other studies report that AMPK has a tumor suppressor role in prostate cancer [19,[23][24][25], so that potent and selective chemical probes [26] will be essential to understand the enigmatic function of AMPK in cancer and other pathologies [2,3,9,12]. AMPK activators mainly bind to the allosteric drug and metabolite site located at the α/β subunit interface and have different isoform selectivity [11]. An inhibitory impact of these compounds on the proliferation of prostate cancer models has been reported but in several cases promiscuous or weak activators were used, which makes interpretation di cult [5,11,12].…”

“…AMPK activators mainly bind to the allosteric drug and metabolite site located at the α/β subunit interface and have different isoform selectivity [11]. An inhibitory impact of these compounds on the proliferation of prostate cancer models has been reported but in several cases promiscuous or weak activators were used, which makes interpretation di cult [5,11,12]. Data with more selective compounds such as MT 63-78 or 991 also suggest a role of AMPK in impairing prostate cancer cell proliferation, via reduction of lipogenesis and independently of CaMMK2 [24,25].…”