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The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models

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Abstract

Purpose

5′ adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis and has been associated with different pathologies, including cancer. Precisely defining the biological role of AMPK necessitates the availability of a potent and selective inhibitor.

Methods

High-throughput screening and chemical optimization were performed to identify a novel AMPK inhibitor. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact as well as the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation.

Results

We identified BAY-3827 as a novel and potent AMPK inhibitor with additional activity against ribosomal 6 kinase (RSK) family members. It displays strong anti-proliferative effects in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of those encoding 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive models. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified several androgen receptor (AR) binding peaks in the HMGCR and PFKFB2 genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux.

Conclusions

The availability of the potent inhibitor BAY-3827 will contribute to a better understanding of the role of AMPK signaling in cancer, especially in prostate cancer.

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Data availability

Complete ChIP-seq data are available at NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) under GSE148358.

Abbreviations

ACC1:

acetyl-CoA carboxylase 1

AMP:

adenosine monophosphate

AMPK:

5′ adenosine monophosphate-activated kinase

AR:

androgen receptor

ATP:

adenosine triphosphate

ATCC:

American Type Culture Collection

CAMKK2:

calcium-calmodulin-dependent kinase 2

ChIP-seq:

chromatin immunoprecipitation DNA-sequencing

CPT1:

carnitine palmitoyl-transferase 1

CRY1:

cryptochrome 1

FASN:

fatty acid synthase

DSMZ:

Deutsche Sammlung von Mikroorganismen und Zellkulturen

GST:

glutathione-S-transferase

HMGCR:

3-hydroxy-3-methyl-glutaryl-coenzyme A reductase

HTRF:

homogeneous time-resolved fluorescence

LIPE:

lipase E

LKB1:

liver kinase B1

PFKFB2:

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2

PPARGC1B:

peroxisome proliferator-activated receptor gamma coactivator 1-beta

PPP2CB:

serine/threonine-protein phosphatase 2A catalytic subunit beta isoform

PRKAR2B:

cAMP-dependent protein kinase type II-beta regulatory subunit

RSK:

ribosomal S6 kinase

SREBF1:

sterol regulatory element-binding transcription factor 1

TET2:

ten-eleven translocation 2

TR-FRET:

time-resolved fluorescence resonance energy transfer

ULK1:

autophagy activating kinase 1

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Acknowledgments

We thank the project team for continuous support. The help of Maria Quanz, Daniel Seifert, Fanny Knoth, Hagen Muckwar, Enrico Spelling, Carolin Pohle, Guido Piechowiak, Sebastian Schulze, Janine Fischer, Vivien Raschke, Pia Stollberg and Daniel Wolleh is gratefully acknowledged. We are indebted to Martin Eilers (University of Würzburg, Germany) for scientific advice. Support with chemical syntheses by Pharmaron is gratefully acknowledged.

Author information

Author notes

  1. Marcus Bauser

    Present address: Janssen Pharmaceuticals, Beerse, Belgium

  2. Simon J. Baumgart

    Present address: Bayer US LLC, Cambridge, MA, USA

  3. Julien Lefranc, Benjamin Bader, Simon J. Holton, Ulf Bömer, Franz von Nussbaum & Marcus Bauser

    Present address: Nuvisan Innovation Campus Berlin, Berlin, Germany

Authors and Affiliations

  1. Bayer AG, Research and Development, Pharmaceuticals, Berlin, Germany

    Clara Lemos, Volker K. Schulze, Simon J. Baumgart, Ekaterina Nevedomskaya, Tobias Heinrich, Julien Lefranc, Benjamin Bader, Clara D. Christ, Hans Briem, Lara P. Kuhnke, Simon J. Holton, Ulf Bömer, Philip Lienau, Franz von Nussbaum, Carl F. Nising, Marcus Bauser, Andrea Hägebarth, Dominik Mumberg & Bernard Haendler

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  10. Lara P. Kuhnke
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  19. Bernard Haendler
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Contributions

Clara Lemos, Volker Schulze and Bernard Haendler contributed to the study conception and design. Medicinal chemistry and computational chemistry: Volker Schulze, Tobias Heinrich, Julien Lefranc, Hans Briem, Lara Kuhnke and Clara Christ were in charge of the medicinal chemistry and computational chemistry part. Clara Lemos, Simon Baumgart, Benjamin Bader, Simon Holton, Ulf Bömer, Philip Lienau and Bernard Haendler were involved in the acquisition of pharmacology data. Clara Lemos, Volker Schulze, Simon Baumgart, Ekaterina Nevedomskaya, Benjamin Bader, Clara Christ, Ulf Bömer and Bernard Haendler were involved in the analysis and interpretation of data (i.e., statistical analysis, biostatistics, computational analysis). Franz von Nussbaum, Carl Nising, Marcus Bauser, Andrea Hägebarth and Dominik Mumberg supervised the study. The first draft of the manuscript was written by Bernard Haendler and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bernard Haendler.

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All authors are/were employees and/or shareholders of Bayer AG.

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Lemos, C., Schulze, V.K., Baumgart, S.J. et al. The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models. Cell Oncol. 44, 581–594 (2021). https://doi.org/10.1007/s13402-020-00584-8

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