2. Academic Validation
  3. Design, synthesis and biological evaluation of a novel tubulin inhibitor SKLB0565 targeting the colchicine binding site

Design, synthesis and biological evaluation of a novel tubulin inhibitor SKLB0565 targeting the colchicine binding site

  • Bioorg Chem. 2020 Apr;97:103695. doi: 10.1016/j.bioorg.2020.103695.
Xi Hu 1,  Lu Li 1,  Qiangsheng Zhang 1,  Qianqian Wang 1,  Zhanzhan Feng 1,  Ying Xu 1,  Yong Xia 2,  Luoting Yu 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China. Electronic address: [email protected].
PMID: 32120073 DOI: 10.1016/j.bioorg.2020.103695
Abstract

A series of 3-(((9H-purin-6-yl) amino) methyl) pyridin-2(1H)-one derivatives were designed, synthesized and confirmed as tubulin polymerization inhibitors. All compounds were evaluated for their anti-proliferative activities on three colorectal carcinoma (CRC) cell lines. Among these compounds, SKLB0565 displayed noteworthy potency against eight CRC cell lines with IC50 values ranging from 0.012 μM and 0.081 μM. Besides, SKLB0565 inhibited tubulin polymerization, caused G2/M phase cell cycle arrest, depolarized mitochondria and induced cell Apoptosis in CRC cells. Furthermore, SKLB0565 suppressed cell migration and disrupted the capillary tube formation of human umbilical vein endothelial cells (HUVECs). Our data clarified that SKLB0565 is a promising anti-tubulin agent for CRC therapy which is worthy of further evaluation.

Keywords

Anti-proliferative; Colchicine binding site; Colorectal carcinoma; Tubulin polymerization inhibitors.

Figures
Products