Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth

Dong Joon Kim, Yan Li, Kanamata Reddy, Mee Hyun Lee, Myoung Ok Kim, Yong Yeon Cho, Sung Young Lee, Jong Eun Kim, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3060-3068
Number of pages9
JournalCancer Research
Volume72
Issue number12
DOIs
StatePublished - Jun 15 2012

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