Development of Potent Adenosine Monophosphate Activated Protein Kinase (AMPK) Activators. Issue 11 (9th September 2015)

• Record Type: Journal Article
• Authors: Dokla, Eman M. E.; Fang, Chun‐Sheng; Lai, Po‐Ting; Kulp, Samuel K.; Serya, Rabah A. T.; Ismail, Nasser S. M.; Abouzid, Khaled A. M.; Chen, Ching‐Shih
• Is Part Of: ChemMedChem. Volume 10:Issue 11(2015:Nov.)
• Page Start: 1915
• Page End: 1923
• Publication Date: 2015-09-09
• Subjects: AMPK -- activators -- antitumor agents -- drug discovery -- lead optimization; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500371
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Previously, we reported the identification of a thiazolidinedione‐based adenosine monophosphate activated protein kinase (AMPK) activator, compound1 ( N ‐[4‐({3‐[(1‐methylcyclohexyl)methyl]‐2, 4‐dioxothiazolidin‐5‐ylidene}methyl)phenyl]‐4‐nitro‐3‐(trifluoromethyl)benzenesulfonamide), which provided a proof of concept to delineate the intricate role of AMPK in regulating oncogenic signaling pathways associated with cell proliferation and epithelial–mesenchymal transition (EMT) in cancer cells. In this study, we used1 as a scaffold to conduct lead optimization, which generated a series of derivatives. Analysis of the antiproliferative and AMPK‐activating activities of individual derivatives revealed a distinct structure–activity relationship and identified59 ( N ‐(3‐nitrophenyl)‐ N ′‐{4‐[(3‐{[3, 5‐bis(trifluoromethyl)phenyl]methyl}‐2, 4‐dioxothiazolidin‐5‐ylidene)methyl]phenyl}urea) as the optimal agent. Relative to1, compound59 exhibits multifold higher potency in upregulating AMPK phosphorylation in various cell lines irrespective of their liver kinase B1 (LKB1) functional status, accompanied by parallel changes in the phosphorylation/expression levels of p70S6K, Akt, Foxo3a, and EMT‐associated markers. Consistent with its predicted activity against tumors with activated Akt status, orally administered59 was efficacious in suppressing the growth of phosphatase and tensin homologue (PTEN)‐null PC‐3 xenograft tumors in nude mice. Together, these findings suggest that59 has clinical value in therapeutic strategies for PTEN‐negative cancer and warrants continued investigation in this regard. Abstract : Small‐molecule AMPK activators : Metabolism reprogramming is a key feature of all cancer cells. Adenosine monophosphate activated protein kinase (AMPK) is an energy sensor; activation of this enzyme can restore normal cell metabolism. Starting with the previously reported AMPK activator OSU‐53 (1 ), an optimization study was conducted, guided by docking studies. Compound59 was identified as the optimal agent, with greater potency than OSU‐53.