Abstract
The serine-threonine mitogen-activated protein kinase kinase family member T-LAK cell-originated protein kinase (TOPK/PBK) is heavily involved in tumor development, cancer growth, apoptosis, and inflammation. Despite the identification of TOPK as a promising novel therapeutic target, no inhibitor of TOPK has yet been reported. In this study, we screened 36 drug candidates using an in vitro kinase assay and identified the novel TOPK inhibitor HI-TOPK-032. In vitro, HI-TOPK-032 strongly suppressed TOPK kinase activity but had little effect on extracellular signal-regulated kinase 1 (ERK1), c-jun-NH2-kinase 1, or p38 kinase activities. HI-TOPK-032 also inhibited anchorage-dependent and -independent colon cancer cell growth by reducing ERK-RSK phosphorylation as well as increasing colon cancer cell apoptosis through regulation of the abundance of p53, cleaved caspase-7, and cleaved PARP. In vivo, administration of HI-TOPK-032 suppressed tumor growth in a colon cancer xenograft model. Our findings therefore show that HI-TOPK-032 is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic against colorectal cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Caspase 7 / metabolism
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Cell Proliferation / drug effects
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Gene Knockdown Techniques
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Humans
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Indolizines / pharmacology*
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Indolizines / therapeutic use
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase 8 / metabolism
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase Kinases / genetics
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Phosphorylation / drug effects
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Poly(ADP-ribose) Polymerases / metabolism
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Quinoxalines / pharmacology*
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Quinoxalines / therapeutic use
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Tumor Suppressor Protein p53 / biosynthesis
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Xenograft Model Antitumor Assays
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antineoplastic Agents
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Indolizines
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N-(12-cyanoindolizino(2,3-b)quinoxalin-2-yl)thiophene-2-carboxamide
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Quinoxalines
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Tumor Suppressor Protein p53
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Poly(ADP-ribose) Polymerases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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PDZ-binding kinase
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Caspase 7