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Updated: Nov 20, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models
Clara Lemos1, Volker K Schulze1, Simon J Baumgart1,2
1Bayer AG, Research and Development, Pharmaceuticals, Berlin, Germany.
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.
Insights
A novel 5' adenosine monophosphate-activated kinase (AMPK) inhibitor, BAY-3827, was identified and shows anti-proliferative effects in prostate cancer. This potent inhibitor aids in understanding AMPK signaling
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- 5' adenosine monophosphate-activated kinase (AMPK) is crucial for cellular energy balance and implicated in cancer development.
- Understanding AMPK's role in pathologies like cancer requires selective inhibitors.
Purpose of the Study:
- To identify and characterize a novel, potent, and selective inhibitor of AMPK.
- To investigate the inhibitor's effects on prostate cancer cell proliferation and lipid metabolism.
Main Methods:
- High-throughput screening and chemical optimization to discover a new AMPK inhibitor.
- Cellular assays, gene expression analysis, and chromatin immunoprecipitation to study cellular impact and signaling pathways.
- Fatty acid turnover analysis via lipid droplet formation assessment.
Main Results:
- BAY-3827 identified as a potent AMPK inhibitor with activity against RSK family members, showing anti-proliferative effects in prostate cancer cells.
- Androgen-responsive upregulation of lipid metabolism genes (HMGCR, FASN, PFKFB2) confirmed, with AR binding sites identified in HMGCR and PFKFB2.
- BAY-3827 down-regulated LIPE, PRKAR2B, and AKT3, inhibited CPT1 family members, and impaired lipid flux.
Conclusions:
- The development of BAY-3827 provides a valuable tool for further research into AMPK signaling in cancer.
- This inhibitor will advance the understanding of AMPK's specific role in prostate cancer progression and therapeutic strategies.
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