2. Academic Validation
  3. Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis

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

  • Cancer Lett. 2019 Mar 31:445:11-23. doi: 10.1016/j.canlet.2018.12.016.
Tiantao Gao 1,  Quanfang Hu 1,  Xi Hu 1,  Qian Lei 1,  Zhanzhan Feng 1,  Xi Yu 2,  Cuiting Peng 3,  Xuejiao Song 4,  Hualong He 3,  Ying Xu 1,  Weiqiong Zuo 1,  Jun Zeng 1,  Zhihao Liu 5,  Luoting Yu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, 17 #3rd Section, Ren Min South Road, Chengdu, 610041, China.
  • 2 Carey Business School, Johns Hopkins University, Baltimore, MD, 21202, USA.
  • 3 School of Chemical Engineering, Sichuan University, Chengdu, 610041, China.
  • 4 Research Center for Public Health and Preventive Medicine, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, 17 #3rd Section, Ren Min South Road, Chengdu, 610041, China. Electronic address: liuzhihao@scu.edu.cn.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, 17 #3rd Section, Ren Min South Road, Chengdu, 610041, China. Electronic address: yuluot@scu.edu.cn.
PMID: 30590102 DOI: 10.1016/j.canlet.2018.12.016
Abstract

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.

Keywords

Apoptosis; DNA-reparation failure; FAK signaling; MAPK signaling pathway; Mitosis failure.

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