2. Academic Validation
  3. Design, synthesis and activity of BBI608 derivatives targeting on stem cells

Design, synthesis and activity of BBI608 derivatives targeting on stem cells

  • Eur J Med Chem. 2018 May 10:151:39-50. doi: 10.1016/j.ejmech.2018.03.054.
Qifan Zhou 1,  Chen Peng 2,  Fangyu Du 1,  Linbo Zhou 1,  Yajie Shi 1,  Yang Du 1,  Dongdong Liu 1,  Wenjiao Sun 1,  Meixia Zhang 3,  Guoliang Chen 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China.
  • 2 Institute of Metabolic Disease Research and Drug Development, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang 110122, People's Republic of China.
  • 3 Institute of Metabolic Disease Research and Drug Development, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang 110122, People's Republic of China. Electronic address: mxzhang@cmu.edu.cn.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang 110016, People's Republic of China. Electronic address: spucgl@163.com.
PMID: 29604543 DOI: 10.1016/j.ejmech.2018.03.054
Abstract

STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and Cancer stemness properties, can inhibit stemness gene expression and kill stemness-high Cancer cells isolated from a variety of Cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC50 = 11.2 μM), but had considerable activity on normal liver cells L-02. Compounds LD-17 (IC50 = 3.5 μM) and LD-19 (IC50 = 2.9 μM) were found to possess significant inhibitory activities and good selectivity. The results showed that compound LD-19 was worthy to investigate further as a lead compound according to its potent inhibitory activity, ideal ClogP value and better water solubility.

Keywords

Antitumor activity; BBI608 derivatives; STAT3 inhibitors; Tumor stem cells.

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