Bayer AG, Research and Development, Pharmaceuticals, Berlin, Germany.
Bayer US LLC, Cambridge, MA, USA.
Cell Oncol (Dordr). 2021 Jun;44(3):581-594. doi: 10.1007/s13402-020-00584-8. Epub 2021 Jan 25.
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.
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.
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.
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.
5' 腺苷单磷酸激活的蛋白激酶（AMPK）是细胞能量平衡的重要调节剂，与包括癌症在内的多种病理有关。准确定义 AMPK 的生物学作用需要一种有效的选择性抑制剂。
采用高通量筛选和化学优化方法，鉴定出一种新型 AMPK 抑制剂。采用细胞增殖和机制测定、基因表达分析和染色质免疫沉淀，研究了该抑制剂在前列腺癌模型中的细胞作用，以及脂代谢与雄激素信号转导之间的相互作用。还通过检查脂质滴形成来确定脂肪酸周转率。
我们发现 BAY-3827 是一种新型有效的 AMPK 抑制剂，对核糖体 6 激酶（RSK）家族成员也有活性。它在雄激素依赖性前列腺癌细胞系中具有很强的抗增殖作用。对 AMPK 信号通路相关基因的分析表明，雄激素应答模型中编码 3-羟-3-甲基戊二酰辅酶 A 还原酶（HMGCR）、脂肪酸合酶（FASN）和 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 2（PFKFB2）的基因表达均被强烈上调，这些基因均参与脂代谢。染色质免疫沉淀 DNA 测序（ChIP-seq）分析在 HMGCR 和 PFKFB2 基因中鉴定出几个雄激素受体（AR）结合峰。BAY-3827 强烈下调雄激素应答前列腺癌细胞系中脂肪酶 E（LIPE）、cAMP 依赖性蛋白激酶 II-β 调节亚基（PRKAR2B）和丝氨酸/苏氨酸激酶 AKT3 的表达。此外，BAY-3827 抑制肉碱棕榈酰转移酶 1（CPT1）家族成员的表达，同时脂流量受损。
有效抑制剂 BAY-3827 的出现将有助于更好地理解 AMPK 信号在癌症中的作用，特别是在前列腺癌中。
