Development of Potent Adenosine Monophosphate Activated Protein Kinase (AMPK) Activators.
Previously, we reported the identification of a thiazolidinedione-based adenosine monophosphate activated protein kinase (AMPK) activator, compound 1 (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 used 1 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 identified 59 (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 to 1, compound 59 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 administered 59 was efficacious in suppressing the growth of phosphatase and tensin homologue (PTEN)-null PC-3 xenograft tumors in nude mice. Together, these findings suggest that 59 has clinical value in therapeutic strategies for PTEN-negative cancer and warrants continued investigation in this regard.
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Room 336, Parks Hall, 500 West 12th Ave., Columbus, OH, 43210, USA.|Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, POB 11566, Abbassia, Cairo, Egypt.
Eman M E
EM
Dokla
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Room 336, Parks Hall, 500 West 12th Ave., Columbus, OH, 43210, USA.
Chun-Sheng
CS
Fang
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Room 336, Parks Hall, 500 West 12th Ave., Columbus, OH, 43210, USA.
Po-Ting
PT
Lai
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Room 336, Parks Hall, 500 West 12th Ave., Columbus, OH, 43210, USA.
Samuel K
SK
Kulp
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, POB 11566, Abbassia, Cairo, Egypt.
Rabah A T
RA
Serya
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, POB 11566, Abbassia, Cairo, Egypt.
Nasser S M
NS
Ismail
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, POB 11566, Abbassia, Cairo, Egypt. Khaled.abouzid@pharma.asu.edu.eg.
Khaled A M
KA
Abouzid
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Room 336, Parks Hall, 500 West 12th Ave., Columbus, OH, 43210, USA. chen.844@osu.edu.|Institute of Biological Chemistry, Academia Sinica, 128 Academia Road Sec. 2, Nankang, Taipei, Taiwan. chen.844@osu.edu.
Ching-Shih
CS
Chen
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D020536:Enzyme Activators; D055372:AMP-Activated Protein Kinases
AMPK; activators; antitumor agents; drug discovery; lead optimization