A novel small molecule inhibits cancer cell proliferation in vitro and in vivo via activation of the protein kinase AMPK


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Hakim Djeha1, Björn Eriksson2, Thomas Edlund2, Fiona McLaughlin1

1Antisoma Research Ltd, Welwyn Garden City, Herts, UK, 2Betagenon AB, Umeå, Sweden

Abstract

A novel small molecule inhibits cancer cell proliferation in vitro and in vivo via activation of the protein kinase AMPK

AMP-activated protein kinase (AMPK) is a key intracellular energy sensor in the cell and the AMPK pathway has been implicated in the regulation of lipid and protein synthesis and cell proliferation. More recently, AMPK has been shown to be a potential drug target for the treatment of human cancer. We have identified a series of small molecules (AL03 series) as potential AMPK activators and evaluated their effect on cancer cell growth in vitro and in vivo.

We demonstrated that compounds of the AL03 series promote Thr-172 phosphorylation of AMPK in cells and inhibit dephosphorylation of p-T172 AMPK by protein phosphatase 2Cα (PP2Cα) in vitro. The AL03 series caused phosphorylation of the eukaryotic elongation factor 2 (eEF2) and inhibited phosphorylation of the p70 S6 ribosomal kinase (p70S6K). We also showed that AL03 compounds have anti-proliferative activity in vitro against various human cancer cell lines as well as efficacy in vivo in a human tumour xenograft nude mouse model without any effect on body weight. When combined with tamoxifen, the AL03 series showed good synergy in a human ER-positive breast cancer cell line in vitro.

We have established that the AL03 series compounds clearly exhibit a therapeutic potential for the treatment of cancer by targeting the AMPK molecular target.