Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis

• Published in: Cancer letters Vol. 445; pp. 11 - 23
• Main Authors: Gao, Tiantao, Hu, Quanfang, Hu, Xi, Lei, Qian, Feng, Zhanzhan, Yu, Xi, Peng, Cuiting, Song, Xuejiao, He, Hualong, Xu, Ying, Zuo, Weiqiong, Zeng, Jun, Liu, Zhihao, Yu, Luoting
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 31.03.2019; Elsevier Limited
• Subjects: Administration, Oral; Animals; Apoptosis; c-Jun protein; Cancer; Cell adhesion & migration; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytotoxicity; DNA damage; DNA-reparation failure; Extracellular signal-regulated kinase; FAK signaling; HCT116 Cells; Humans; JNK protein; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Malignancy; MAP kinase; MAP Kinase Signaling System - drug effects; MAPK signaling pathway; Metastases; Metastasis; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - genetics; Mitosis; Mitosis failure; Oral administration; Protein kinase; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proteins; Signal transduction; Transcription factors; Tumorigenesis; Xenograft Model Antitumor Assays; Xenografts; FAK signaling; MAPK signaling pathway; DNA-reparation failure; Mitosis failure; Apoptosis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.12.016

The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell–originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy. Here, we report the development of a TOPK selective inhibitor SKLB-C05, with subnanomolar inhibitory potency. In vitro, SKLB-C05 exhibited excellent cytotoxicity and anti-migration and invasion activity on TOPK high-expressing CRC cells and induced cell apoptosis. These activities could attribute to its inhibition of TOPK downstream signaling including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), as well as downregulation of FAK/Src- MMP signaling. Furthermore, SKLB-C05 disrupted cell mitosis and blocked CRC cell cycle. In vivo, oral administration of SKLB-C05 at concentrations of 20 and 10 mg kg−1·day−1 dramatically attenuated CRC tumor xenograft growth and completely suppressed hepatic metastasis of HCT116 cells, respectively. Thus, these findings suggest that SKLB-C05 is a specific TOPK inhibitor with potent anti-CRC oncogenic activity in vitro and in vivo. •SKLB-C05 selectively inhibit TOPK kinase with subnanomolar potency.•SKLB-C05 exhibit anti-proliferative activity only on TOPK-positive CRC cells.•SKLB-C05 markedly inhibit tumor growth and hepatic metastasis of CRC.•SKLB-C05 down-regulate TOPK mediated signaling pathway.•FAK/Src-MMPs signaling promote CRC metastasis and SKLB-C05 inhibit the pathway.