BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors

The AMP-activated protein kinase (AMPK) is a sensor of the energy status in the cells, playing a key role in controlling their metabolism. For many years, AMPK was mainly perceived as a tumor suppressor in agreement with being a component of the LKB1 tumor suppressor cascade, which inhibits mTORC1. However, in the last few years, some studies suggested that AMPK might actually exert a pro-tumorigenic role in certain contexts. For instance, Liu and colleagues demonstrated that dysregulated MYC expression renders tumor cells sensitive to AMPK depletion (Liu et al, 2012. Nature). The authors showed that, due to their increased anabolism, MYC-dependent cells rely on AMPK to restore ATP levels and to prevent an energy crisis that results in apoptosis and cell death. Here we report the discovery of a new lead structure for the inhibition of AMPK by biochemical high throughput screening. The optimization of this lead structure towards potency and selectivity led to the probe compound BAY-3827 and the use of this tool compound to evaluate the therapeutic potential of AMPK inhibition in MYC-dependent tumors. To demonstrate a cellular effect of BAY-3827 an HRTF® assay (Homogeneous Time Resolved Fluorescence, cisbio) for phospho-Acetyl-CoA carboxylase (p-ACC, Ser79), a direct substrate of AMPK, was used. ACC phosphorylation was strongly inhibited by BAY-3827 in COLO 320DM and IMR-32 cells. However, despite its high potency, BAY-3827 failed to inhibit the proliferation of cells with dysregulated c-MYC or N-MYC. In conclusion, we have identified a potent and selective AMPK inhibitor. Despite demonstrated inhibition of AMPK kinase activity, BAY-3827 treatment did not translate into antiproliferative activity in MYC-dependent cells. While we could not confirm our initial hypothesis, one might speculate that inhibition of AMPK might be of therapeutic utility in other biological contexts. Therefore, the availability of potent and selective inhibitors, as described here, will contribute to further insight into the potential of AMPK inhibition as a therapeutic target in cancer. Citation Format: Clara Lemos, Volker K. Schulze, Benjamin Bader, Clara D. Christ, Hans Briem, Oliver Politz, Florian Prinz, Simon Holton, Tobias Heinrich, Julien Lefranc, Philip Lienau, Arne Scholz, Franz von Nussbaum, Carl Friedrich Nising, Dominik Mumberg, Marcus Bauser, Andrea Hagebarth. BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5873.